A (possible) solution to Covid-19 - <AUTHOR> https://www.tillett.info/2020/04/05/a-solution-to-covid-19/ <comment><USER4> I'm not qualified to assess the risk, but if the there's indeed ADE (antibody dependent enhancement),[1][2] people once infected with a milder strain may suffer from more severe symptom from the deadlier strains, thus killing more people in the end.

I'm wondering how we may rule out this worst case scenario.

[1] Is COVID-19 receiving ADE from other coronaviruses? [https://www.sciencedirect.com/science/article/pii/S128645792...](https://www.sciencedirect.com/science/article/pii/S1286457920300344)

[2] New blood tests for antibodies could show true scale of coronavirus pandemic [https://www.sciencemag.org/news/2020/03/new-blood-tests- anti...](https://www.sciencemag.org/news/2020/03/new-blood-tests-antibodies- could-show-true-scale-coronavirus-pandemic)

<comment><AUTHOR> ADE is more a problem for the vaccine approaches. It is one reason we may never have a vaccine for this disease.

Hard to rule out worst case scenarios, we just have to work with what we have and make hard choices.

<comment><USER5> >ADE is more a problem for the vaccine approaches. It is one reason we may never have a vaccine for this disease.

This is at least partly why there are no SARS/MERS vaccines. There's a paper I'll try to dig up where 4-8 (can't remember) modified vaccine candidates were tested in multiple animal species, and in each case except one, immunity was conferred but exposure to the virus lead to a dangerous autoimmune response which destroyed lung tissue.

<comment><USER6> That's not ADE as I understand it. ADE is where the virus gets grabbed more easily by cells thanks to the antibodies on it proving handles.

<comment><USER5> Well yes, because of ADE the normal antibodies released by the immune response immediately increase the replication rate so you have a far more severe reaction upon infection than you would otherwise.

That's why I'm waiting for confirmation of immunity. So far I've only seen increasing numbers of reports of reinfection but that may just be faulty testing.

</comment></comment></comment></comment></comment><comment><USER7> I posted and deleted a few comments. I don't know what to make of this and it's getting controversial. If it could be helpful, I'd love to improve it. I just don't know where it fits in ongoing discussions by prominent researchers on analysis of strains and types.

Three things that jump out at me:

a) You'll get more credibility from having a thorough lit review than from listing credentials. Linking to magazine articles from journalists on genetic variations, when there's academic research to cite, is a little bewildering.

b) You don't identify something harmless by just testing asymptomatics. This is counterintuitive, but a great example of the Wason selection task:

[https://en.wikipedia.org/wiki/Wason_selection_task](https://en.wikipedia.org/wiki/Wason_selection_task)

You would probably want to survey the rate of variants in asymptomatics in a certain community, then compare that with the rate of variants in fatal cases in the same community to look for significant differences (and be fully prepared not to find any significant differences beyond chance, a real and likely possibility).

c) I'm still not sure what the author is specifically recommending we do next. Researchers are looking for functional variants, we don't have one to distribute yet, so we should do more sequencing. Ok, great. From what populations? How many geographic areas? Where do we get the samples? There are bottlenecks in sample collection, how do we overcome those? Given (b), how can we get more samples from fatal cases, to compare virulence to those in the general population? Task overloaded hospitals to send us additional samples from dying patients? Is there another way we can get this info?

I don't want to dismiss this out of hand, this might be a good area for additional focused research. I do think there are some key unanswered questions though, and currently a worrying disconnect with the current state of research on variants.

EDIT: Daniel, I know you're going through the comments here, and some of them have gotten pretty harsh, sorry for that. I genuinely hope you're on to something, and are able to continue to refine the post into a more robust and specific proposal using all this feedback, despite the tenor of some of the comments. That's really the best case for all of us, so good luck.

<comment><AUTHOR> Just woke up (I am in Australia). I expect some harsh comments as the idea is controversial. To your specific points.

a) The post was intended for a lay audience, not other scientists directly. The reason I didn't write a scientific paper on this is it would sink without a trace as most scientists and doctors are too conservative. It is quite a radical idea and while scientifically sound, it will take mavericks outside of science to see this done. For better or worse it will take the efforts of someone like on of the tech billionaires to push this forward.

b) If I had to choose one aspect that gets most commonly confused by people who read the idea it would be the reason for searching only mild/asymptomatic cases. This is purely an efficiency issue. In an ideal world we would sequence the strains in all cases, look to see if we can find mutants with deletions, and then see what was the clinical outcome of those infected with that strain. If we find that all cases of a particular mutant are mild/asymptomatic then we would have our candidate.

Because we live in a constrained world where it is not possible to sequence all cases, where should we first look? Since we are looking for a mutant that only causes mild/asymptomatic cases we can exclude patients with serious symptoms as a first pass. Once we find a candidate strain that has the right sort of mutation we can then sequence all cases in the local area, both serious and mild to get the full clinical picture. This will make the search much more efficient.

c) I am recommending that we put b) into action and get on with specifically looking for an attenuated (only causes mild disease) strain ASAP. If we find one then we can discuss what to do next, but the first step is to get started.

The good news is this can be done quickly and relatively cheaply provide we have the will and the support of someone with the clout to make it happen. It won't be easy, but it can be done.

<comment><USER8> Tech billionaire for publicity, maybe. But just getting a guide ready might help more - everybody with a moderate amount of cash and access to the medical system somewhere can start doing this in his back yard.

</comment></comment></comment><comment><USER9> How does the Iceland data suggest the hypotheses that 1) an attenuated strain exists in the wild and 2) it provides immunity to the worse strain? It's asserted in the post, but I don't see it. It seems likely to me their experience isn't any different from any other country's, and they're just testing more.

The idea in the post is obviously a good one if it can be done, it's just that it seems like a generic idea that should be considered for any viral pandemic, which makes me wonder why it's not already an approach people are working on.

<comment><AUTHOR> It doesn't which is why I never claimed it did???

As for why people aren't working on this idea I don't know. Maybe someone is and they will send me an email and I can update my post. I would certainly be extremely happy with this outcome.

<comment><USER9> I was responding to this from your blog post:

> This data suggests a simple and testable hypothesis – there are natural > strains of SARS-CoV-2 in the world that have mutated to be non-pathogenic > (asymptomatic), but are still infective and will provide immunity to the > more pathogenic (deadly) strains.

From the structure of the post it sounded like "this data" referred to Iceland plus the Wuhan study.

If you only meant the Wuhan study then apologies for misunderstanding.

<comment><AUTHOR> Yes both. The Icelandic data suggests there is genetic diversity in SARS-CoV-2 and the Wuhan data suggests there are strains that are less pathogenic.

There is also a Singapore study that has identified strains with large gene deletions, but I haven't yet updated the post to include it [0].

0\. [https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1....](https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1.full.pdf)

<comment><USER10> Here's a post from late February that enumerates 42 known strains of 2019-nCoV as a phylogenetic tree: [https://nextstrain.org/narratives/ncov/sit- rep/2020-01-30?n=...](https://nextstrain.org/narratives/ncov/sit- rep/2020-01-30?n=5)

I'm a lay person here, but it seems a foregone conclusion that viruses experience frequent mutation, and that a novel virus infecting a new host species for the first time is going to see a relative explosion in mutations due to the extreme increase in the number of opportunities for it to occur.

</comment></comment></comment></comment></comment><comment><USER11> This seems risky but worth consideration.

Can you provide peer / concept review from virologists?

A few items of feedback:

\- You could use a title that includes a distinct word to identify your proposed solution: "Using accentuated COVID-19 strains as a (possible) solution". This helps people to communicate and refer to the idea concisely.

\- The top three paragraphs may be known to your target audience; consider allowing the reader to get straight to your point.

\- It took me a while (certainly to the Q&A section) to grasp that attenuated virus strains are different from dangerous ones. Explaining this (perhaps in a brief sentence, then repeated and elaborated in a more detailed paragraph) near the top may also help.

\- Further references (especially peer review from respected authors) may help gain traction. Decision makers can be -- sensibly -- risk averse in global crises like these.

Good luck!

<comment><AUTHOR> I am a virologist - well I have published many papers in this area. I have a PhD in molecular microbiology and have been a tenured professor (I now work in the biotech sector). This is not intended to be a scientific paper, but a layman's summary of the idea so non-technical people can understand the idea.

It is not risky to go looking for a naturally attenuated virus. This is the first step that needs to happen.

<comment><USER12> Wouldn't an attenuated strain vaccine still require years of paperwork and clinical trials too?

<comment><AUTHOR> Yes. This is why I am suggesting an alternative. It is all in the blog post.

<comment><USER13> This is an attenuated live vaccine, though. So the risks are similar or worse than just doing a real, engineered vaccine.

If it's mere paperwork, we can solve that with a regular vaccine just as fast. And the regular vaccine would be more likely to be safe, even at an early stage. (Note: I'm a rando, not a medical or biological professional.)

<comment><USER14> if bureacracy held up the spread of a live coronavirus, we wouldn't be in this mess

<comment><USER13> The proposal is to _intentionally_ apply a live virus to people, so _absolutely_ there are bureaucratic barriers to this (and for good reason). There is no a priori reason why this should have less red tape than a dead virus.

If we're just going to ignore any regulations and bureaucracy for a live virus (like this proposes), we can do the same for a dead virus.

<comment><AUTHOR> The reason why this should be able to advance faster than a normal vaccine approach is that we will have epidemiological data that it is safe in humans. Sure it would be nice to have double blinded placebo controlled data, but good epidemiology data is still data on which a regulatory decision could be made. In the current circumstances I think this will satisfy the regulators.

</comment></comment></comment></comment></comment></comment></comment></comment><comment><USER15> A naturally attenuated strain would still be regulated. In the US, 21 USC §321(g):

> (1) The term "drug" means… (B) articles intended for use in the diagnosis, > cure, mitigation, treatment, or prevention of disease in man or other > animals;

CBER would be the responsible center for the FDA. Other countries have analogous regulations.

Could you come to market with a naturally attenuated strain? Yes. Would it take less time? Not really, because you don't get to do an "end run around the regulations" as you put it in another comment. The logistics of making sure it works and then setting up the supply chain and quality systems are what take the most time. There are no shortcuts in medicine.

<comment><AUTHOR> There are plenty of shortcuts in medicine. Think how you would stop this strain from being spread by individuals once it was identified. This strain will spread no matter what the FDA says.

Personally I think the regulatory authorities would rapid approve it based on the epidemiology data collected in the process of finding the strain. The FDA has already shown that it can move faster than its usual glacial pace given sufficient motivation.

The much more important question is when are we going to start seriously looking for such a strain?

<comment><USER16> Serious question: are we not? People are sequencing these things like crazy (c.f. the nextstrain.org data). Epidemiologists are working like mad to come up with data on severity in regions all over the globe. Virologists everywhere are dropping what they're doing otherwise to work on covid.

It sorta strains reason to argue that none of these people thought of looking for an attenuated strain.

Isn't the simpler truth just that finding one takes a lot of ground work that's already being done, but hasn't born fruit yet?

<comment><USER17> they re probably not sequencing asymptomatic people's virus, it would require some specific expedition. it doesn't even sound hard or expensive

reply to @ajross:

how would they know someone is asymptomatic? afaik they are mostly testing people who have symptoms , and their contacts (who will have contracted the same , symptomatic strain)

I think in germany they did antibody testing, or PCR of swabs of people who mostly no longer had a live virus infection to sequence. also, it seems the idea has merit; and i havent read about any team looking for this specific method (identify gene deletions and tracing). It certainly doesn't hurt (and doesnt cost much) to try

btw sweden is doing a survey of live infections in stockholm, however i don't think that they sequence the viruses

to @danieltillet:

maybe post about it in reddit on r/covid19, some epidemiologists hang out there for the latest news

<comment><USER16> Are they not? That seems like a pretty obvious experiment to do.

For reference: I have a family member in virology. He reports that everyone he knows is now working on covid, mostly because if they don't they can't come to work on anything. The biggest problem is finding subjects that will produce a paper of any kind. I really don't think research bandwidth is the issue here.

I guess I have to repeat the question as its converse: is there any evidence that this is not happening? If it isn't, let's figure out the right people to pressure and not just discuss it on HN. And if it is, maybe we should let the experts do their work without pretending to have had their ideas for them?

<comment><AUTHOR> If you know anyone working on my idea please let me know as I will update my blog post. Nothing would please me more than to learn that someone is already doing this on a serious level.

</comment></comment></comment></comment></comment></comment><comment><USER18> Virus can be asymptomatic for a number of reasons. Host factors, such as age, (speculation) history of the previous coronavirus but not covid-19 infections, etc.

Going after covid-19 genomes in a group of asymptomatic and symptomatic 70+ years old with sampling from different regions/countries may give us better data.

Finding a mutated strain which never gives symptoms in old people from diverse locations, diet, health status etc. is the holy grail of this approach.

<comment><AUTHOR> Yes. What we really want is a strain that has infected a whole lot of people and all of them have had a mild case.

<comment><USER19> You probably won't find that... You might find a strain where 99.9% of people get a mild case.

Who is going to be the person to recommend deliberately spreading that strain to the world population, knowing that 0.1% of the world, 7 million people, will end up in a hospital and die?

Sure, overall, fewer people might die, but the reality is whichever world leader makes that call has effectively just signed a death warrant for 7 million people. That isn't the way to get re-elected.

<comment><AUTHOR> I think we can do better than 0.1% death rate. In principle there is no reason we can't find a strain that is no more dangerous than the coronaviruses that cause the common cold.

One thing is certain and that is unless we go out and look we won't find anything.

<comment><USER20> @danieltillett

I could quickly put together a team focused on southern Nigeria and Ghana to find through word of mouth, medical records, contact tracing lists and social media, people who have experienced covid-19 symptoms and are likely to have had the disease. My team would also collect samples from people in the worst affected areas who are asymptomatic. In this way, we could collect data and enough samples to isolate a(?the) virus if any.

Do you know any organisations that could provide funding and support for this ?

<comment><AUTHOR> It is probably best to contact me offline. My email details are on my website.

</comment></comment></comment></comment></comment></comment><comment><AUTHOR> I have posted this again as dang asked me to put it up again.

Happy to answer questions about the idea, but I am most interested in find collaborators to make it happen ASAP.

<comment><USER21> I just sent your article to my contacts at the White House, Department of Defense, DARPA and a couple of other acronym agencies. I sent this to Director level people (or just under) at those agencies.

No guarantees (they are all swamped). I hope they respond and put you in touch with the right people.

<comment><AUTHOR> Thanks. This is the problem I have run into which is all the right people are so busy at the moment that they don't have time to look at something like this from someone like me.

<comment><USER21> Yes.

I can confirm that your information got to one of my contacts at the White House. He replied saying he would distribute it to the right people. Your guess is as good as mine as to what happens from there. Even people within the White House have trouble penetrating through various layers due to just how busy everyone is (as well as security, etc.).

<comment><AUTHOR> Thanks once again.

</comment></comment></comment></comment></comment><comment><USER22> I totally missed it from the article but how is he going to tell the deadly strain from the less deadly one? I mean I understand how they can tell the difference between the two strains. But how to tell that some particular strain is less deadly? To the best of my understanding the only way to get there is to sequence the virus from statistically significant number (~10^5 ??) of carriers including the significant proportion of those with asymptomatic cases. Not realistic IMHO.

<comment><USER23> Not to mention relying on each person's account of the severity of the symptoms, and coding that into a dataset that corresponds to the sequencing results. You need a LOT of asymptomatic people with the strain in order to draw any strong conclusions.

The upside is, you may draw other very interesting conclusions while collecting data for this mission, and be able to "pivot" if you will.

</comment></comment><comment><USER24> You make this statement: "The most important thing to note is that such a virus would not be a vaccine from a regulatory perspective."

Can you provide any evidence to back up this statement? If you were to start intentionally infecting people with a (naturally) attenuated strain claiming that it will confer immunity I suspect authorities would request you get regulatory approval.

If you're approach does require regulatory approval. What advantage does your approach have over those currently in developement? Some of them are just bits of the virus (mRNA that codes for the spike protein) packaged with a delivery mechanism [1].

It's a plausible approach, that has been tested in animal studies. There are a number of other, similarly plausible vaccines entering human trials.

It is however deemed to be too high risk to just start giving the vaccine to large numbers of people. So the vaccine will have to go through (an accelerated) trial process. It will then likely be given to at risk groups (health care professionals), before becoming widely available. Most experts expect this to take at least 16 months (which would be a world record).

Your approach would have the same issues as are present with any other vaccine.

If regulatory authorities are willing to skip trials for your approach, then the same should apply to other vaccines under development.

[1] [https://www.modernatx.com/modernas-work-potential-vaccine- ag...](https://www.modernatx.com/modernas-work-potential-vaccine-against- covid-19)

<comment><AUTHOR> You are looking at this from the wrong perspective. If people start spreading this attenuated strain around on their own what are the regulatory agencies going to do?

Even if you wanted to go down the regulatory pathway for some reason it still has a number of advantages over other approaches.

1\. We would know it is safe in humans before we began.

2\. We would know what mutations make the virus less pathogenic.

3\. Once used it would drive the pathogenic strains to extinction.

4\. It will be work in poor countries that can't afford or distribute a conventional vaccine.

5\. It will infect and protect those that are not deliberately infected through contact with others.

<comment><USER24> > What are regulatory agencies going to to do?

If you were to start doing this without regulatory approval, the most likely outcomes seems that you'd be arrested [1]. Do you have anything that suggests otherwise?

> 1\. We would know it is safe in humans before we began.

The regulatory requirements for "knowing it is safe in humans" are currently quite high. As things stand, I would expect trials to be required. Can you provide any evidence to suggest trials wouldn't be required?

You want to know how the vaccine effects individuals with pre-existing conditions etc. etc. And, as there's always some risk, you want to be sure that the vaccine is effective.

> 2\. We would know what mutations make the virus less pathogenic.

Large scale sequencing of the virus, in individuals and populations will be interesting. Being able to link this patient outcomes is also interesting. And might help in vaccine development. It would be interesting to have a large dataset of viral sequences from asymptomatic individuals. Can we see clear differences between asymptomatic and symptomatic individuals? This would be an interesting dataset, but I'm not sure that the results would be as clear as "look this deletion exists in a sub-population of asymptomatic individuals". Would be a cool dataset and an interesting project though. There seems to be a lot of NGS data [2] available. This might be a suitable starting point for such a project.

> 4\. It will be work in poor countries that can't afford or distribute a > conventional vaccine.

If a vaccine is available, then I suspect there will be sufficient international support to make it widely available. Having an active outbreak anywhere in the world would likely be deemed an unacceptable risk, given the potential for further mutation.

[1] [https://www.theverge.com/2020/3/26/21195236/fbi-doj- arrest-f...](https://www.theverge.com/2020/3/26/21195236/fbi-doj-arrest-fake- coronavirus-vaccine-cure-covid-19-keith-middlebrook)

[2] [https://www.ncbi.nlm.nih.gov/genbank/sars- cov-2-seqs/](https://www.ncbi.nlm.nih.gov/genbank/sars-cov-2-seqs/)

<comment><AUTHOR> I am not going to be spreading the virus around so why would I be arrested? Actually once a "safe" strain was identified and could be tested for it would be impossible to stop it being spread by individuals on their own to those they know.

As we have seen with the whole HCQ fiasco regulations have a habit of getting lowered once there is data, even poor data. If we contact trace everyone who has been infected with the attenuated strain we will get some good data on the safety of the strain. It might not be 100% safe, and we might have some questions, but that is a discussion we can have once we find the strain.

We need to make some hard choices here between certainty and action. Waiting for certainty is a choice that carries a very high cost.

<comment><USER24> Perhaps I've missed something in your argument then. I'd need to understand exactly how you are planning to promote the spread of the attenuated form. If you're talking about a "sequencing driven" Pox party [1] then I suspect you will run into issues. Particularly if you were to say that the Pox party will infect you with an attenuated form of the virus and vaccinate.

Both the diagnostic (sequencing or otherwise) and claim that you are vaccinating individuals would seem like they'd require regulatory approval. But I'd be interested in evidence that suggests this is not the case in a modern context.

Overall, it seems like the idea is as dangerous as deploying an untested mRNA vaccine. Because of this, I'd suspect that regulatory or other authorities would get involved.

[1] [https://en.m.wikipedia.org/wiki/Pox_party](https://en.m.wikipedia.org/wiki/Pox_party)

<comment><AUTHOR> I am not planning on doing anything other than trying to look for the attenuated strain. How it is used is for others - what I am suggesting is once such a strain is found is it will be impossible to stop people spreading it around on their own.

<comment><USER24> But you do seem to be suggesting that "people spreading it around on their own" is a "solution to Covid-19"?

Otherwise, what is your plan for this attenuated strain? Don't get me wrong, I think large scale sequencing or COVID19 is interesting. But think that attempting to spread a attenuated strain without regulatory approval is probably a very bad idea.

<comment><AUTHOR> Unregulated spread by individuals is a solution, just not the one I think would be implemented if such a strain were found.

I think it much more likely that the regulatory agency would quickly approve the use of the strain on the basis of the epidemiological data gathered in the process of finding it.

<comment><USER25> > I think it much more likely that the regulatory agency would quickly approve > the use of the strain on the basis of the epidemiological data gathered in > the process of finding it.

Have you had experience with dealing with said regulatory agencies?

<comment><AUTHOR> Unfortunately yes and they normally move at a glacial pace and demand 100% certainty about everything. I do have faith that they are capable of moving faster when the need is as urgent as the need right now.

</comment></comment></comment></comment></comment></comment></comment></comment></comment></comment><comment><USER26> I like your idea a lot. It seems that a 12 nucleotide insertion mutation is responsible for a lot of the Covid-19 virulence. If such a large mutation is possible, how would we prevent your loss of function asymptomatic strain from reverting its mutation in the wild? How big of a mutation are you envisioning? Is it impossible for it to be reverted in the wild or just unlikely?

[https://www.nature.com/articles/s41591-020-0820-9](https://www.nature.com/articles/s41591-020-0820-9)

<comment><AUTHOR> I think 12 nucleotides is too small, I would be happier with something north of 30. There have already been strains identified with a deletion of 382 bases [0].

0\. [https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1....](https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1.full.pdf)

</comment></comment><comment><USER27> > More than 50% of the people infected with SARS-CoV-19 are asymptomatic (i.e. > they have no illness).

Note: asymptomatic at the time of testing. They may still develop symptoms over time.

[https://www.icelandreview.com/sci-tech/is-icelands- coronavir...](https://www.icelandreview.com/sci-tech/is-icelands-coronavirus- testing-showing-that-50-of-cases-have-no-symptoms/)

[https://twitter.com/cmyeaton/status/1246196001775460358](https://twitter.com/cmyeaton/status/1246196001775460358)

<comment><AUTHOR> Yes this is true. For the purpose of my idea it doesn't matter if the person is asymptomatic or they just have a mild case. What is important is the strain identified doesn't put people in hospital.

<comment><USER28> The key here is that the vulnerable population needs to tolerate it, too.

<comment><AUTHOR> Technically they don't provided we can get the herd immunity up to a decent level in the rest of the population.

While it would be a good idea if the mutated strain was no more dangerous than a common cold coronavirus, we could drive the dangerous strains to extinction without having to infect the vulnerable.

<comment><USER29> Very difficult to get herd immunity up to a decent enough level without putting the vulnerable portion of the population in great danger though. Most countries are approaching something like 0.1% or 0.2% of the population having been infected. Herd immunity requires 70% - 80% immunity. About 350x - <USER2> more than what's happened already.

Also the whole thing presumes that immunity is lasting. Some of the data is showing that may not be the case.

<comment><AUTHOR> The level of herd immunity needed is related to the R0 which is a function of behaviour. This is a really complex topic to discuss, but it is only one we can have once an attenuated strain is found.

Of course the other factor is who is a vulnerable person is a factor of the pathogenicity of the viral strain.

</comment></comment></comment></comment></comment></comment><comment><USER30> The results of a study in austria with 1500 randomly selected citizens have just been published, just 5 have been found to be currently infected with SARS-CoV2.

The conclusion is that the prevalence of asymptomatic cases is about 0,32%, CL95 is 0,12-0,76%.

Link (in german): [https://www.sora.at/nc/news-presse/news/news- einzelansicht/n...](https://www.sora.at/nc/news-presse/news/news- einzelansicht/news/covid-19-praevalenz-1006.html)

<comment><USER31> This goes contrary to what other studies have found. In the Stockholm metropolitan area they found that 2.5% percent of the population was infected [1]. In in a community in Germany, which was the epicenter of the outbreak for a time, they found that 15% of the population tested positive for antibodies [2]. In Iceland they found that 88-93% of the infections are undetected [3].

[1] [https://www.folkhalsomyndigheten.se/nyheter-och- press/nyhets...](https://www.folkhalsomyndigheten.se/nyheter-och- press/nyhetsarkiv/2020/april/resultat-fran-undersokning-av-forekomsten-av- covid-19-i-region-stockholm/)

[2] [https://www.land.nrw/sites/default/files/asset/document/zwis...](https://www.land.nrw/sites/default/files/asset/document/zwischenergebnis_covid19_case_study_gangelt_0.pdf)

[3] [http://www.igmchicago.org/wp- content/uploads/2020/04/Covid_I...](http://www.igmchicago.org/wp- content/uploads/2020/04/Covid_Iceland_v10.pdfhttp://www.igmchicago.org/wp- content/uploads/2020/04/Covid_Iceland_v10.pdf)

<comment><USER30> I don't think it is actually contrary to those other studies. The austrian study randomly selected among the whole population whereas the german study used a cluster connected to a hot-spot. IMO it is measures like social distancing in place for more than 3 weeks at the time of sample-taking in austria that reflect in the data.

<comment><USER31> It does. The german study was conducted in a town that was relatively heavily tested during its outbreak, and only recorded 2.5% official infections in the population of that town, so the german study showed the actual number to be 7 times as high. This Austrian study found this number to be only ~2.5 times as high. Germany and Austria overall seem to test fairly similarly.

<comment><USER30> The austrian number says currently active cases are probably 2.5 times as much as official numbers.

German study says in a community linked to an outbreak, there are 14% immune and 2% to be shedding viral DNA.

Austrian study didn't include antibody test (yet).

</comment></comment></comment></comment></comment><comment><USER32> Stupid question: if you only search people with mild or even asymptomatic cases, how does that even tell you something about the virus? Should you not also search in (many) severe cases for the candidate, to exclude it from the list of dangerous virii?

<comment><AUTHOR> There are no stupid questions, just stupid politicians.

We are looking for an attenuated strain and that will be found in people with a mild case. We could sequence all cases, but we would exclude any strain that puts someone in hospital so it is a waste of resources to sequence viruses from people in hospital. From a practical perspective it is better to concentrate on people with only mild cases.

<comment><USER32> But honestly, if you only look into people with mild cases, how do you know the virus causes these mildness?

If I pick 1k people with mild cases at random, I will find pretty much any strain that currently is in circulation. How do I know which strain is harmless?

<comment><AUTHOR> You don't, but what you are looking for is a virus with a largish deletion in an essential gene. You then go and look for anyone in contact with this person and check them and then expand out to the whole local area. If everyone infected with this strain has a mild illness they you have hit the jackpot.

I do describe this in my blog post.

<comment><USER33> I think GP's point was that if you have a candidate it would also make sense to use sequences from the hospitalised to try and confirm your strain didn't put them there.

Aka this being one mechanism by which you confirm it is only producing mild illness. There's a limited amount you can find out by asking because nobody knows what strain they had.

<comment><AUTHOR> You really want to find every single person who has been infected with the mutant strain and find out how sick they got. If you find a mutant that infected 10,000 people and didn't cause any serious illness then you have a pretty good idea it safe.

<comment><USER34> I think the point is that you have to sequence people in the hospital as well, otherwise you won't know if that particular strain is safe or not.

If it is a rare strain, how will you know if it's safe? Seems like it would have to be a rare strain with thousands of cases and hospitalizations in that population are extremely rare.

Sampling bias and other confounding factors would be a real problem in this search, at least from a statistical point of view, imo.

I also think finding everyone who has been infected with a strain isn't feasible, at best you are sampling from the population.

<comment><AUTHOR> You actually want to screen all people in the local area for the strain that may have it. If all the people have had a mild case and none of them are in hospital then you have something special.

</comment></comment></comment></comment></comment></comment></comment></comment><comment><USER35> I see two problems with this approach, both political / social:

\- No one will want to be the one "deploying" the attenuated strain in a human and then be responsible for some unforeseen death (even if it's just 1 in a billion). Utilitarianism is not widespread nor socially accepted. Even less so in politicians, who are quite risk averse.

\- There is no lobby supporting it. There's no $$ to be made and the "vaccine" is basically free.

<comment><USER36> _No one will want to be the one "deploying" the attenuated strain in a human and then be responsible for some unforeseen death (even if it's just 1 in a billion). Utilitarianism is not widespread nor socially accepted. Even less so in politicians, who are quite risk averse._

I would give them more credit, especially in a situation where the status quo includes so many deaths. I was impressed with how readily most states licensed self-driving vehicles, knowing that there would certainly be deaths. Their rationality here likely came from seeing tens of thousands of people dying on the roads each year.

</comment></comment><comment><USER37> I am not an expert, so I apologize if these are a dumb questions, but here goes:

1) Wouldn't natural selection result in a milder strain crowding out a more deadly strain? After shelter in place lifts, people with a mild strain will be more likely to go out and spread the virus whereas people with the deadly strain will be more likely to stay home sick.

2) Is there any consensus on whether we become immune to COVID after getting it (e.g. if we get a mild strain will we really be immune to a deadly one)? I've heard different opinions and I'm wondering what the leading hypothesis is at the moment.

Thanks!

<comment><USER38> That sounds correct, but "scientifically" we have to spend million of dollars and months of time to say for sure.

</comment></comment><comment><USER39> This reminds me of a story 20 years ago when Pittsburgh Steelers (American football) announcer Myron Cope ran into head coach Bill Cowher...

Myron said, "I see that Lee Flowers is playing today after a high ankle sprain 2 weeks ago. But I thought that high ankle sprains took 4 weeks to heal. What gives?"

Coach Cowher replied, "4 weeks is true, Myron, for the _first_ high ankle sprain. But if you recall, Lee had a high ankle sprain on the same foot last year. And since subsequent high ankle sprains only take 2 weeks to heal, he's ready to play."

Myron paused and asked, "Then why don't you just take the whole team out in February and sprain all their ankles?"

(We laughed 20 years ago. Nobody's laughing today.)

<comment><USER40> This reminds me of the old joke that, because the possibility of there being _two_ bombs on a plane is infinitesimally small, you should always bring your own bomb with you.

</comment></comment><comment><USER41> Another strain that might be less deadly: [https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1....](https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1.full.pdf)

Also it is a paper from Singapore which should avoid the China negative bias.

<comment><AUTHOR> This is exactly the sort of strain we want to be looking for all though we want a strain that doesn't come from hospitalised patients. This deletion is still too pathogenic for our needs, but it does prove these deletion strains are out there. If we look we will find.

</comment></comment><comment><USER42> How would you allow the harmless strain to spread without also spreading the deadly strain? If you relax or reverse social distancing, wouldn't the deadly strain also have a chance to spread widely again? It seems like you'd need to manually administer this strain to millions of people, or have very carefully administered 'contagion parties' where everyone is pre-screened for the deadly strain, while everyone else keeps social distancing.

<comment><USER43> > you'd need to manually administer this strain to millions of people

Yes. And how would that compare to the various trillions in stimulus to keep a choking world economy afloat, never mind the deaths that could be avoided?

I don't understand posts like this, they say "if we had a good solution, how could we possibly use it?"

<comment><USER42> I think you're reading too much into my post, I was just wondering how to safely carry out this idea.

One reason I was wondering is that manually administering the virus to people seems more akin to a vaccine in nature.

<comment><AUTHOR> Only if you consider hanging out with someone a vaccine.

As I mentioned in my reply to you it will be impossible to stop this strain from being deliberately spread by people on their own.

<comment><USER25> Wouldn't the same social distancing measures that keep the dangerous strain at bay keep the "good" one from spreading? And vice versa.

<comment><AUTHOR> Yes they would, but if people know their friends have the mild version they might choose to break the social distancing rules and go and visit them for a tea and nice close chat.

</comment></comment></comment></comment></comment></comment><comment><USER44> I don't think the mutations are the reason for asymptomatic cases. Coronaviruses mutate very slowly.

More likely, viral load, immune system strength, overall age and the genetics of the person infected are what determines if the infection is fought off before any symptoms are shown

<comment><USER45> For my own understanding: where can I read about how coronaviruses mutate slowly?

<comment><USER46> It is deemed to have an RNA repair mechanism. This is suggested by analogy with other coronaviruses [1,2] and the length of its RNA of ~30k nucleotides while the upper limit for RNA without repair mechanism seems to be 10k [3]. The german wikipedia cites [4] which I found nicer to read.

[1] [https://en.wikipedia.org/wiki/Coronavirus#Replication](https://en.wikipedia.org/wiki/Coronavirus#Replication) [2] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984655/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984655/) [3] [https://de.wikipedia.org/wiki/Coronaviridae#Genom](https://de.wikipedia.org/wiki/Coronaviridae#Genom) [4] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3127101/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3127101/)

</comment></comment></comment><comment><USER47> There are several pre-clinical studies with live attenuated viral vectors and replicating viral vectors going on against SARS-CoV-2. [https://www.who.int/blueprint/priority-diseases/key- action/l...](https://www.who.int/blueprint/priority-diseases/key-action/list- of-candidate-vaccines-developed-against-sars.pdf?ua=1)

Developing attenuated-virus vaccines is by screening serially propagated SARS- CoV-2 for reduced pathogenity has also been suggested already.

1\. The outbreak of SARS-CoV-2 pneumonia calls for viral vaccines [https://www.nature.com/articles/s41541-020-0170-0](https://www.nature.com/articles/s41541-020-0170-0)

2\. Regla-Nava, J. A. et al. Severe acute respiratory syndrome coronaviruses with mutations in the E protein are attenuated and promising vaccine candidates. J. Virol. 89, 3870–3887 (2015). [https://www.ncbi.nlm.nih.gov/pubmed/25609816/](https://www.ncbi.nlm.nih.gov/pubmed/25609816/)

Authors idea of spreading the attenuated virus is based on the idea that if the immediate COVID-19 disease can be avoided, increasing viral load in population is smaller risk. I think that's the weak point. If the vaccine is developed and the virus establishes itself in the population, the number of people getting infected will be lower overall and less people will get severe disease due to natural immunity + vaccine.

ps.

> appears to be killing between 1% to 3.5% of the people it infects

Author is confusing case fatality rate (CFR) with infection fatality rate (IFR). Infection fatality ratio seems to be something like 0.6% according to recent estimates. IFR estimates seem to go down over time.

<comment><AUTHOR> This is not a proposal for a live attenuated vaccine.

These numbers on the death rate are not mine, but what has been reported in the scientific literature. Probably the best numbers come from South Korea where they have done a pretty good job of tracking down everyone infected. There the fatality rate is around 1.8%.

Even if the true death rate is 0.6% that still means the deaths of nearly 50 million people worldwide.

<comment><USER47> Even the sources you cite give case fatality rate not infection fatality rate. You are confusing the two.

<comment><AUTHOR> The true infection rate is irrelevant. Nobody knows what it is right now and by the time we do it will be too late.

<comment><USER47> We are talking infection fatality rate not infection rate.

Infection fatality rate is number of people who die after they are infected. That's one of the most important numbers and it can be estimated. It's different from case fatality rate. Number of people diagnosed with COVID-19 who die.

You started your argument trying to argue based on your understanding of what the infection fatality rate is.

<comment><AUTHOR> Nobody knows the true infection fatality rate. Probably the best estimate we can make is from South Korea where they have done a pretty good job of testing everyone infected. There the infection fatality rate is 1.8% and rising as the cases age out and people in the ICUs die.

<comment><USER47> > Nobody known the true infection fatality rate.

It can be estimated with increasing accuracy.

> There the infection fatality rate is 1.8% and rising as the cases age out > and people in the ICUs die.

You continue citing case fatality rate (CFR) numbers and call them infection fatality rate numbers (IFR). Can you please go back to your sources and read what they say. I bet they are case fatality rates. In South Korea one IFR estimates put the number around 0.4 and 0.7%.

Here are some IFR estimates:

1\. Estimating the infection fatality rate of COVID 19 in South Korea by using time series correlations [https://figshare.com/articles/Estimating_the_infection_fatal...](https://figshare.com/articles/Estimating_the_infection_fatality_rate_of_COVID_19_in_South_Korea_by_using_time_series_correlations/12083322)

2\. Estimating the infection and case fatality ratio for coronavirus disease (COVID-19) using age-adjusted data from the outbreak on the Diamond Princess cruise ship, February 2020 [https://www.eurosurveillance.org/content/10.2807/1560-7917.E...](https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.12.2000256)

3\. Using early data to estimate the actual infection fatality ratio from COVID-19 in France [https://www.medrxiv.org/content/10.1101/2020.03.22.20040915v...](https://www.medrxiv.org/content/10.1101/2020.03.22.20040915v2)

4\. Robust Estimation of Infection Fatality Rates during the Early Phase of a Pandemic [https://www.medrxiv.org/content/10.1101/2020.04.08.20057729v...](https://www.medrxiv.org/content/10.1101/2020.04.08.20057729v1)

<comment><AUTHOR> These lower estimates are all estimates.

Really it is not important from the perspective of doing something about this pandemic as a huge number of people will die at all estimated levels.

<comment><USER47> Maybe you can now correct the "killing between 1% to 3.5% of the people it infects" part. It's horribly misleading.

IFR < CFR and IFR estimates go always down over time and never up due to the skewed nature of the data. Antibody tests are coming in already and based on them you get very accurate numbers.

<comment><AUTHOR> I am going to update the post this morning - lots of good feedback from people here on which sections are confusing. I will update this section :)

</comment></comment></comment></comment></comment></comment></comment></comment></comment></comment><comment><USER48> I want to argue that the flaw in this is with the ability to find any strain that consistently causes only minor symptoms. If you infect a whole group of people with Covid-19 then we would see a distribution of severity from no symptoms to lethal. This broad spectrum is really just it's statistical variance (whatever the underlying distribution really looks like).

It is worth comparing this to things like SARS. The distribution of SARS symptoms would be pretty narrow - everyone gets really sick. So the variance for SARS is small compared to Covid-19. The same could be observed for influenza or rhinoviruses.

The problem with a "milder" Covid-19 is that it might still have the same massive variance in symtpom severity. It might kill less people, but it would still be morally bankrupt to let it spread. In fact, it might be preferable to not reduce the mean severity, but just decrease the variance so it never gets nasty enough to kill without being immuno-compromised.

<comment><USER17> This paper argues on the basis of symptoms that there might be a milder strain that has dominated some countries vs others

[https://www.medrxiv.org/content/10.1101/2020.03.28.20036715v...](https://www.medrxiv.org/content/10.1101/2020.03.28.20036715v2)

<comment><USER49> There may be other explanations such as past use of vaccines for other diseases, that varies country to country.

<comment><USER48> Yes. Or just variations in our immune systems. Immune systems are incredibly complex systems. It is difficult to overstate just how complex and varied they are. And they differ between individuals to an amazing extent.

If immunity is important to symptom severity, it may manifest as some weird correlation you might find in a cross-sectional study. Maybe gluten intolerance or a history of acid reflux will be a marker that lets you know what your risk of severe disease are.

</comment></comment></comment></comment><comment><USER50> In one of the article comments there is an interesting suggestion on reviving the research on DRACO[1]:

> In cell culture, DRACO was reported to have broad-spectrum efficacy against > many infectious viruses, including dengue flavivirus, Amapari, and Tacaribe > arenavirus, Guama bunyavirus, H1N1 influenza, and rhinovirus, and was > additionally found effective against influenza in vivo in weanling mice. It > was reported to induce rapid apoptosis selectively in virus-infected > mammalian cells while leaving uninfected cells unharmed.

They even had a crowdfunding campaign on Indiegogo[2] but as usual, nobody cares about infectious diseases until the pandemic...

Now the crowdfunding seems moved to another page[3]

[1] [https://en.wikipedia.org/wiki/DRACO](https://en.wikipedia.org/wiki/DRACO)

[2] [https://www.indiegogo.com/projects/1641241](https://www.indiegogo.com/projects/1641241)

[3] [https://riderinstitute.org/discovery/](https://riderinstitute.org/discovery/)

<comment><USER51> Why did they choose indiegogo over traditional medical research funding?

<comment><USER52> The source that wikipedia cites says the following:

"However, research on DRACOs has entered the well-known "Valley of Death" in which a lack of funding prevents DRACOs, and many other promising new drugs, from being developed and advancing toward human medical trials. To progress DRACOs research it needs to be demonstrated against clinically relevant viruses (i.e; HSV). To that end an IndieGoGo campaign ([http://igg.me/at/EndTheVirus](http://igg.me/at/EndTheVirus)) was started on October 13, 2015."

They don't seem to elaborate on what the hell they mean by the valley of death.

[http://www.prweb.com/releases/2015/10/prweb13018147.htm](http://www.prweb.com/releases/2015/10/prweb13018147.htm)

<comment><USER53> Basically there is funding for early research, and for drugs that are really close to release, but the years in between (the drudgery) aren't very interesting to investors so capital is hard to come by to keep projects alive.

An acquaintance is $600m into a new type of Malaria testing and his funding is slowing, but is frustrated because he feels he is closer then ever. Frankly im amazed he got this far, thats a lot of burn.

Basically funding for drug research is all screwy!

</comment></comment></comment></comment><comment><USER54> Apparently China has at least one hospital full of asymptomatics.

[https://www.straitstimes.com/asia/east-asia/mystery-of- long-...](https://www.straitstimes.com/asia/east-asia/mystery-of-long-term- patients-confounds-wuhan-doctors)

</comment><comment><USER55> > it would be much better to just post a sample of the virus to everyone for > example

If COVID-19 is human malware, then this is a human software update.

<comment><USER56> At what probability of bricking during update would you stay on the old vulnerable version?

</comment></comment><comment><USER57> How do we know that a less deadly strain actually provides some immunity to a more deadly strain? That seems like an assumption here.

<comment><USER58> His assumption is based on live-attenuated vaccines. The measles vaccine being one of those. All the early vaccines where like that. The process only requires heat inactivation. So you end up with a dead or almost dead virus, which can't replicate anymore. Your immune system recognizes it as a foreign agent, makes antibodies to tag it for removal.

Today we prefer to immunize with a part of the virus structure, which end up doing the same thing.

<comment><USER57> Still seems like an assumption until its tested/proven. I'd prefer a more evidence based approach, evidence from this virus.

<comment><AUTHOR> You can only get evidence if you go out and collect the evidence. I am proposing a way we can actually collect this evidence. Saying something won't work because there is no evidence when you haven't look for any evidence is not very logical.

<comment><USER57> Just questioning assumptions, in a healthy skepticism kind of way. I have no expertise here. There is a lot of speculation and general fud surrounding covid-19, seems right to question potential 'solutions' when we are light on facts. To be clear, I never said it wouldn't work, I'm saying that it looks like you assume it will work.

<comment><AUTHOR> I most certainly have not assumed it will work, in fact I say there is a pretty good chance it won't. What I do think it could work and that the cost in minor compared to the payoff if it does work.

<comment><USER57> In which case, we need to think about Medical Ethics. Do we start experimenting with you and your loved ones?

<comment><AUTHOR> Nobody is being experimented on or proposed to be experimented on. The proposal is to go and look for an attenuated strain and then decide what to do with it if we find one.

<comment><USER57> [https://www.npr.org/sections/coronavirus-live- updates/2020/0...](https://www.npr.org/sections/coronavirus-live- updates/2020/04/25/844939777/no-evidence-that-recovered-covid-19-patients-are- immune-who-says)

</comment></comment></comment></comment></comment></comment></comment></comment></comment><comment><USER59> You say

> The reason why is immunity to respiratory viruses (like corona) doesn't last > long – 6 months to 2 years.

I haven't read anything like this before. It seems like you're extrapolating from the flu vaccine, which doesn't last because the flu mutates too quickly. Coronavirus mutate much slower and the thought is that we'll likely only need one vaccine. Have we actually found any less deadly strains? My understanding is that there have been mutations, but all are small and as far as we can tell superficial. You would likely need to create such a mutation and then you're back in vaccine trial territories, except dozens of labs that are experts on this have a head start.

<comment><USER60> [https://www.nature.com/articles/d41586-020-00798-8](https://www.nature.com/articles/d41586-020-00798-8)

> If humans do develop immunity, how long does it last?

> That's another big unknown. Immunity is short-lived for the coronaviruses > that cause common colds; even people who have high levels of antibodies > against these viruses can still become infected, says Stanley Perlman, a > coronavirologist at the University of Iowa in Iowa City.

> The evidence is more equivocal for the two other coronaviruses that have > triggered epidemics: those that cause severe acute respiratory syndrome > (SARS) and Middle East respiratory syndrome (MERS). Perlman says his team > has found that after people recover from MERS, their antibodies against the > virus drop precipitously. He also says that his team has gathered data — not > yet published — showing that SARS antibodies are still present in the body > 15 years after infection. But it's not clear whether this immune response is > enough to prevent reinfection. "We don't have good evidence of long-lasting > immunity, but we also don't have really good data from both SARS and MERS," > Perlman adds.

<comment><AUTHOR> This is a huge problem for the whole vaccine approach and is one of the reasons that it may not be possible to create a conventional vaccine.

</comment></comment></comment><comment><USER61> I've been thinking about this a few days ago when I went into the wikipedia rabbit hole about vaccinations and inoculation.

A few questions:

\- How about the dengue fever scenario? (Immunity to less pathogenic strain can cause more severe reaction with a different strain). Can we asses the risk somehow?

> Apart from the time it will take to develop, trial, and mass produce a > vaccine (12-18 months), it is unlikely that any vaccine will be practicable. > The reason why is immunity to respiratory viruses (like corona) doesn't last > long – 6 months to 2 years

Is there any proof that this is the case with this virus?

Is is possible to do the infection outside the human body?

<comment><USER62> We just don't know. Either case (short immunity like the common cold, or permanent immunity) is possible.

<comment><USER61> It seem the permanent immunity is unlikely [https://youtu.be/4EUZEtJHQhE?t=639](https://youtu.be/4EUZEtJHQhE?t=639)

</comment></comment></comment><comment><USER63> Sounds like a good idea.

Another interesting possible solution which can be used now but is a bit unproven is to use hydroxychloroquine + zpak + zinc or some variation on that on people with symptoms or who test positive as it seems to reduce viral spreading.

Bit controversial but the results in Marseille look quite good - the infection rate in those tested has roughly halved recently while France as a whole is going up. [https://madeinmarseille.net/64805-covid-19-didier-raoult- res...](https://madeinmarseille.net/64805-covid-19-didier-raoult-resultat- chloroquine/) [https://www.mediterranee- infection.com/covid-19/](https://www.mediterranee-infection.com/covid-19/)

And the anecdotal reports from the Zeleko guy are good even if people think he's a nut.

Also in the Rome area "every single person with Covid-19 that has early signs, like a cough or a fever for example, is now being treated with the anti- malaria drug." Which may provide data going forward [https://www.trustnodes.com/2020/03/29/italy-finally- starts-m...](https://www.trustnodes.com/2020/03/29/italy-finally-starts-mass- treatment-with-hydroxychloroquine)

Anyway unproven but may be a way forward if the results prove good.

</comment><comment><USER64> Agreed that the risk:reward ratio here would be worth it. This sounds super promising. That being said, how is it known that having had the mutated strain provides immunity to the dangerous strain?

<comment><AUTHOR> The reason why it would provide immunity is all the structural proteins would be the same. To our immune system it would look like the same virus as the pathogenic strains.

This is not really anything unusual and is exactly how viral live vaccines work. The vaccine for live polio and measles work exactly this way.

</comment></comment><comment><USER65> Pooling could be used to more rapidly test the asymptomatic population:

[https://github.com/EFavDB/pooling](https://github.com/EFavDB/pooling)

<comment><AUTHOR> Even better than pooling is griding [0].

0.[https://twitter.com/rwade300/status/1247340350076628992](https://twitter.com/rwade300/status/1247340350076628992)

<comment><USER66> If B2 and D4 are positive, then in the marginals B,D,2,4 will show positive, but you don't know which of B2, B4, D2, D4 are positive.

<comment><AUTHOR> Yes that is true, but when the case rate is low this is not a common problem. The ideal size of the grid is adjusted to expected case rate.

If you get ambiguity then you just move those samples across to a new grid (in locations that won't be ambiguous) and test again.

</comment></comment></comment></comment><comment><USER67> (caveat: amateur)

I think this is a great idea to get community involvement upon. I'm sure you know there's a network of researchers on Twitter (I'm aware of the one centered around the Krogan lab in UCSF i.e. @KroganLab), and on Reddit (reddit.com/r/covid19) that have been posting ideas back and forth. Consider posting there.

I like your idea because it circumvents a number of ethical issues, but may be time/resource consuming. Another approach but one that quickly hits those ethical issues during testing would be to knockout immunosuppressant genes as popularly described by: [https://www.nytimes.com/interactive/2020/04/03/science/coron...](https://www.nytimes.com/interactive/2020/04/03/science/coronavirus- genome-bad-news-wrapped-in-protein.html) (preprint [https://www.biorxiv.org/content/10.1101/2020.03.22.002386v3....](https://www.biorxiv.org/content/10.1101/2020.03.22.002386v3.full.pdf+html)). Perhaps mice model? An in between approach that might be better, would be to target your search by looking for changes that likely inactivates the immunosuppressant genes.

I and I'm sure many others dearly hope your approach works. Godspeed sir.

</comment><comment><USER68> This might be a naive question, but could this strain be created by some kind of gene editing?

<comment><AUTHOR> Yes it could, but we wouldn't know what edits to make. What this idea is using is nature to tell us what mutations make the virus less dangerous.

<comment><USER68> I see, thanks!

</comment></comment></comment><comment><USER17> Considering that we are now in a shutdown, and assuming that most symptomatic people do get tested and isolate themselves, doesnt that mean there is pressure for asymptomatic strains to evolve and keep spreading faster in the population anyway? they would be more likely to exist in the early epidemics, specifically south korea which aggressively quarantines people, but does not impose lockdowns, letting the asymptomatic spread

<comment><AUTHOR> There is really no selection pressure on the current dangerous strain right now. If it was killing 50-60% of people infected then yes the selection pressure would be there, but at a death rate of 1.5%-2% there basically is very little selection pressure on the timescales we are interested in.

It doesn't really matter to us today if this virus eventually becomes less dangerous in the next 500 years. We need to speed things up a little.

<comment><USER17> > If it was killing 50-60% of people infected then yes the selection pressure > would be there

it isnt killing, but it's isolating them, preventing its spread

<comment><USER69> That's already baked in to human responses to suspected COVID-19 though, and a chance mutation to a less lethal strain would be unlikely to change human responses to an outbreak in a way which benefited the virus' ability to spread.

<comment><USER17> i assume we re looking for asymptomatic people, they won't have quarantined themselves

</comment></comment></comment></comment></comment><comment><USER70> Can't the attenuated strain mutate back to a strong dangerous one after we spread it? (Hope this isn't a stupid question)

<comment><USER71> In theory any coronavirus could, including the 4 we consider absolutely harmless.

In fact, with existing attenuated virus approaches that eventually becomes the problem, the "last mile" of this approach usually sees you needing a real vaccine to cap off the disease. Otherwise the virus kinda circulates around in a tight enough cycle that you see most if not all eventual mutations including dangerous ones that kill. Communities using attenuated virus vaccination approaches for Polio faced this in recent times, for example. And it becomes a problem in places where you can't get people to afford or accept the real vaccine.

Anyway it's a tried/tested approach to solving a pathogen problem, so it's hardly some crazy idea this person has. They do point out the there will be specific types of mutations that are less likely to mutate back if you read the whole article.

<comment><AUTHOR> The problem with polio back mutating is limited to one of the three strain in the live vaccine and is due to the mutations not being deletion mutations. The live polio vaccine was developed before people knew this and for regulatory reasons the problem has never been fixed.

This problem is easy to avoid these days.

<comment><USER71> I have no reason to believe you're wrong, I just wanted to point out that we (as a whole community of scientists etc.) can observe an entire range and lifecycle of this approach and that we're aware of the risks based not only on theory but on practice.

Personally I see your proposal as a relatively worthy endeavor to consider.

</comment></comment></comment></comment><comment><USER72> This is why scientists and mathematicians never make it as politicians in the USA

You may have the best idea in the world, but your presentation is terrible, the rambling is terrible, the assumption you are the only person to think of this is terrible and the urge to get the attention of someone important to pay for it is terrible.

The sad truth is you need to fit your idea into the size of a tweet, write the long version elsewhere linked. If you can't do that, someone else can and will and their idea will win over yours because you can't get attention rambling like that

And governments are never going to purposely infect their populations, if you think anti-vaxers are bad, imagine when people in the USA have the choice not to get the injection, 99% of the fox news viewers will refuse and the president will say "well you can if you want but I won't" (I mean he won't even stop shaking hands or wear a mask)

<comment><AUTHOR> You are welcome to rewrite my post and even claim the idea as your own if you want. Make it as short as a tweet (which I have done by the way) and send it out into the world.

</comment></comment><comment><USER41> Another relevant link: [https://www.medrxiv.org/content/10.1101/2020.04.14.20060160v...](https://www.medrxiv.org/content/10.1101/2020.04.14.20060160v1)

<comment><USER41> And another about mutation rate being a lot higher than thought: [https://www.scmp.com/news/china/science/article/3080771/coro...](https://www.scmp.com/news/china/science/article/3080771/coronavirus- mutations-affect-deadliness-strains-chinese-study)

</comment></comment><comment><USER73> Any back of envelope math on how much this "search" will cost? Does it require someone with Bill Gates sized bank account or are you mentioning him because you know he is specifically active in this area of philanthropy/very influential?

<comment><AUTHOR> Yes. Less than a million dollars - I actually can afford to pay the whole thing myself. The only reason to get someone like Bill Gates involved it to get access to the samples and the required political capital to make it happen.

<comment><USER63> Cool. I hope you get it done.

</comment></comment></comment><comment><USER74> It seems the reason the vaccine will take so long (12-18months) to develop is because it needs to be tested for long-term safety which takes a trial with long-term monitoring. As this is essentially a sort of (active) vaccine, how do you propose ensuring it's long-term safety? It seems you'd run into essentially the same problem as with developing the vaccine.

<comment><USER75> It seems to me that the whole article describes to me an alternative way to find a vaccine . Maybe someone can enlighten me: aren't there vaccines that are simply rather harmless mutations/relatives of the virus but trigger the same immune reaction?

<comment> grey-area Yes, there are

[https://en.m.wikipedia.org/wiki/Attenuated_vaccine](https://en.m.wikipedia.org/wiki/Attenuated_vaccine)

</comment></comment></comment><comment><USER76> A huge problem I see with this is that already circulating coronaviruses cause immunities as short as 3 months. While the SARS virus seems to cause much longer immunity (same for MERS), this may be linked to the strong symptomes that people have, thus may be due to a stronger immune reaction. Asymptomatic cases and people with mild symptoms may therefore be immune only for a short time. If this is the case, any herd immunity strategy will achieve not much but endanger many many people.

<comment><AUTHOR> This is the exact problem my idea solves.

Please take some time to read through the whole proposal again. I know this sound snarky, but yours is a really common response that has been addressed.

<comment><USER34> I did read through your entire proposal, this is a legitimate question, and is not address in your proposal. It is definitely not the problem your proposal is aimed at solving.

The question posed is would an attenuated virus create a much short immunity reducing efficacy of the overall approach. It seems like the only answer can be we don't know, we'd have to look at that.

<comment><USER76> Exactly. His whole proposal is based on the assumption that an attenuated strain imuunizes enough people long enough. This has been possible in other diseases. But for example not the common cold, and not only because many different virus belong to that category.

So yes, I read your proposal. No, this is not addressed.

</comment></comment></comment></comment><comment><USER77> "We have a choice of taking some small risk now, or face the certainty of a much worse problem later. Time to accept some risk and do something."

Agreed 100%.

What about simply letting the people who young and healthy or immune go about their lives?

Letting the young and healthy get sick and then become immune is essentially using an attenuated human instead of an attenuated virus. Same outcome though.

This would both build herd immunity and keep the economy going.

<comment><AUTHOR> This seems to the Swedish plan. What I have noticed with this plan is that a lot of vulnerable Swedes have died from this plan. I think we can do better.

<comment><USER77> Please post numbers instead of sensational posturing next time.

Sweden has no quarantine and has been averaging around 400 to 500 new cases daily while UK quarantined everyone and has 4000 to 5000 new cases daily.

The interesting thing is that the UK has 60 million people while Sweden has 10 million people.

So according to those numbers...how effective is quarantine?

<comment><AUTHOR> Sweden is not doing too much testing either. I am not sure if the UK is a good comparison as they are not really in lockdown at the moment. I think the better comparison is to Norway and Denmark.

</comment></comment></comment></comment><comment><USER78> I hear a lot of ideas, which ignore the indications from both China and South Korea about re-infection. Nobody for sure knows how long the immunity lasts. Also, people could be asymptomatic/mild-symptom, just because they have a strong immune response, not because the strain is less deadly. How do you quantify who is immunosuppressed and who has a well-functioning immune system?

<comment><AUTHOR> Yes, but this idea of mine is not one of these ideas.

<comment><USER78> I read your idea, but it doesn't address the exact points I listed - <USER3> a "less deadly" strain and having fingers crossed that immunity persists. So far, many have insufficient antibody counts and get reinfected. I just saw a number around 20%.

<comment><AUTHOR> There are lots of things we don't know right now. This is not a reason for not acting.

If my proposal works we don't need to worry about immunity persisting because the dangerous strains will be driven to extinction.

</comment></comment></comment></comment><comment><USER79> South Korea somehow avoided the whole lockdown approach.

<comment><USER80> Can we confidently say what has or hasn't been avoided by anyone? It seems a little early to be counting our chickens.

</comment></comment><comment> _-___________-_ > SARS-CoV-2 (the virus that causes COVID-19) appears to be killing between 1% > to 3.5% of the people it infects

The article that this text links to discusses case fatality rate, which is _not_ the percentage of people the virus infects that die. This is a fundamental and very important difference, especially given that you later note the percentage of asymptomatic people.

<comment><AUTHOR> Nobody knows the true asymptomatic rate, but even if it is 5o% the number of people that will be killed is massive.

Let's not get caught up on the final death rate and let's look at what we can do right now.

<comment> _-___________-_ The OP literally opens with a misinterpreted statistic. It links to an article about CFR and claims that the values are IFR instead of CFR. This is not "getting caught up on something", I'm pointing out a fundamental error.

Most serious estimates of IFR are between 0.1 and 0.6%. The OP should be edited to either correctly state that COVID-19 kills between 1 and 3.5% of _identified cases_ , or be updated to use numbers that are not misleading.

<comment><AUTHOR> These IFR numbers you quote are also incorrect as there are many people infected who have not yet had time to die. The best estimate probably comes from South Korea (they seem to be picking up nearly all cases with their massive contact tracking and testing) where the death rate is at 1.8% and trending higher.

<comment> _-___________-_ Then why not link to a study about the IFR in South Korea? My point is that the claim you make about the percentage of people who are infected that die is not supported at all by the article that the claim links to, which only discusses the percentage of confirmed cases that die.

<comment><AUTHOR> Because the whole issue of IFR is irrelevant to my argument and the range provided is wide enough to cover all estimates.

</comment></comment></comment></comment></comment></comment><comment><USER81> In theory the idea would work. People being cooperative enough is where I'm skeptical. I assume anyone in the high risk group would volunteer to receive the less-dangerous strain and when the incentive of lowering risk of death is obvious. I speculate young people wouldn't volunteer unless they have a health issue placing them in the high risk group.

<comment><USER82> >I speculate young people wouldn't volunteer unless they have a health issue placing them in the high risk group.

I suspect lots of young people would happily volunteer if it meant their life could return to normal. Heck, I'd bet even for the current strain, with a ~0.1% risk of death for young people, quite a few people would volunteer to get it if it meant they could get out of lockdown.

<comment><USER81> I'm not disagreeing with that opinion. I just haven't observed young adults taking the lockdown seriously.

I personally work from home (as one of the privileged few being a programmer) and when I do go outside I take social distancing serious. My health in general isn't great although I'm not old (early 30s) and which is why I don't leave my apartment much anymore. I live in a college area and young adults are still going over to each others apartments and without practicing social distancing when going out to buy groceries. I'm in Quebec for context. I've heard it isn't much different in the USA.

Maybe the (possible) solution could work without young people on board.

<comment><USER82> >I live in a college area and young adults are still going over to each others apartments and without practicing social distancing when going out to buy groceries.

That's my point: the young adults don't want to comply with the social distancing, so if someone said "hey, if you let me infect you with this virus that has a 1/50,000 chance of killing you, you can no longer get/transmit the more dangerous strain so you don't have to social distance any more", a lot would take the offer.

<comment><USER81> Why wouldn't they just say "no" and continue not social distancing?

<comment><USER82> They don't want to be fined? I thought in most places with a lockdown they're fining people who don't follow social distancing requirements.

</comment></comment></comment></comment></comment></comment><comment><USER83> The Netherlands is testing with plasma from a recovered patient right now:

Source: [https://nos.nl/artikel/2330036-nederlandse-coronapatient- hee...](https://nos.nl/artikel/2330036-nederlandse-coronapatient-heeft-plasma- met-antistoffen-ontvangen.html)

NB: I am NOT a microbiologist and do not know how far this is related.

<comment><USER84> It's not particularly related.

Plasma contains molecules that contribute to immunity. The donation transfers those molecules from the donor to the recipient. It doesn't directly confer any immunity to the recipient, it reduces the amount of virus circulating in their body, giving their own immune system more time to respond.

</comment></comment><comment><USER85> Isn't this just one of many ways to produce a vaccine, so won't it need the same long term trials for safety and effectiveness that any type of vaccine needs? Reducing this this time somehow is what I think is needed.

<comment><AUTHOR> I address this in the post. The answer is no it is not just another vaccine approach.

<comment><USER85> Do you mean this "virus would not be a vaccine from a regulatory perspective"? In that case it is just another vaccine approach, but one that you alledge falls outside the current regulations. Do you think the regulations need to change due to the emergency?

<comment><AUTHOR> This is a question that really is unimportant at this point. What matters is what we can do today.

<comment><USER86> It's extremely important because it's a question a lot of people are going to be asking. You'll need a good answer as to why this approach should not be subject to similar regulations as vaccines otherwise this will go nowhere.

<comment><AUTHOR> Is the FDA regulating the spread of the dangerous version?

More seriously there is nothing for the FDA to regulate here. It is a natural virus spreading in a natural way.

<comment><USER85> How can you claim it would be spread in a natural way? The intention is to spread it deliberately.

<comment><AUTHOR> Because the attenuate virus we are looking for would be one that can spread naturally. Of course humans might choose to help it along once it is found by say hanging out with an infected person. Lots of options here

</comment></comment></comment></comment></comment></comment></comment></comment><comment><USER87> Daniel, Why can't we use the virulent strain but in extremely small quantity? Like 1/1000 of the typical viral load?

<comment><USER62> That's covered by the post: because the person who received the small viral load will infect others and give them a large viral load.

<comment><USER87> Thanks. How about a quarantine say 14 days after the small viral load delivery.

Maybe we can do that to a subset of healthy young population so that they can go back to work without risking others?

I don't have much idea about either virology or molecular biology. Just curious.

</comment></comment></comment><comment><USER88> > "Can't we just wait for a vaccine?

> "No. Apart from the time it will take to develop, trial, and mass produce a > vaccine (12-18 months), it is unlikely that any vaccine will be practicable. > The reason why is immunity to respiratory viruses (like corona) doesn't last > long – 6 months to 2 years. We would have to keep vaccinating everyone in > the world every year (or maybe every 6 months if we are unlucky). "

I am not sure I agree with this. I am taking the annual flu shot, along with all the members of my family. I would be fine with an annual, or semiannual, coronavirus shot.

<comment><USER89> Poor countries can't afford that.

</comment></comment><comment><USER90> Perhaps a first step is to simulate a population where several variations of the virus exist, and where people set out to get infected by those who are believed to host a "safe" variation. What is the likelihood that interaction between the variations and people's mistaken beliefs screw this up?

</comment><comment><USER91> From the comments on your site:

> One thing is certain with the current situation is we need to take some > risks if we are going to solve it quickly.

Looking for quick answers in a crisis is really risky. There is a natural push to try to get things back to normal as soon as possible, but developing an attenuated vaccine (even with a potential strain already in existence), takes a lot of time and testing.

I certainly agree that we should be trying to sequence every variation we can find in the wild, but even if everything works just right, it will take a lot of time. I haven't followed enough of the reports, but how many strains have been identified thus far?

Another issue is that even just getting the reagents to collect and passage the virus is difficult as they are all needed for clinical testing. So working with live (even attenuated) virus is very difficult at the moment. But this highlights a reason why it is so critical to study these topics when we aren't in crisis mode. Much of the current vaccine work has been adapted from earlier SARS-CoV research.

But this approach of finding a weakened strain (or generating one), is a good idea to be attempted in parallel. (I'm sure that someone is trying to passage the virus though a different host to attenuate it as we speak). The first step is to try and sequence as much as we can from the wild, but this has its own logistical difficulties. Hopefully there is a research study going on that is trying to collect as many samples as possible now, so that we can sequence later when things have calmed a bit (because there is likely going to be a second round).

I don't intend to sound so negative on this. I largely agree that this is one avenue that needs to be studied. And from your background, I know you understand these risks/concerns. I worry about the larger public though. My main concern is that this concept can be very risky, especially with an already scared public looking for quick answers. Seriously, the last thing we need is people intentionally trying to get infected in the hope of getting a less lethal strain. This isn't a cowpox scenario. I guess my hesitation comes down to me not liking the idea of taking too many risks for the sake of doing it quick. That's been known to come back and bite people.

<comment><AUTHOR> Not doing something is very risky too. This is a problem with only hard choices.

</comment></comment><comment><USER92> Interesting, I wonder if this could explain to some extend different death ratios that are currently blamed on hospital capacity, age etc. - in other words, what if Italy has spread of more danerous mutation kind and Japan has spread of less dangerous one.

<comment><USER93> The global sequencing effort makes this reasonably straightforward to study. While the prevalance of different strains does vary geographically, new international tranmission events occur _so frequently_ that most places have a handful of circulating strains already [0]

[0] [https://nextstrain.org/ncov/europe](https://nextstrain.org/ncov/europe)

</comment></comment><comment><USER94> Is there a guarantee it would not associate with other viruses (possibly other strains, or even something worse?)

And the lack of testing to "save time" actually does not look like a good idea for a live virus you want to give to the whole earth.

<comment><USER95> IMHO, he is not going to give new virus to the whole earth, the virus already exists hence freely speading by itself from host to host. The idea is to speed up spreading of "good" virus to preempt spreading of a bad one and finally make the last to extinct.

</comment></comment><comment><USER96> Brilliant && simple. Why nobody is acting on it?

Please correct spelling:

..I now work..

..a number of papers..

Thank you, please spread the word (url).

<comment><AUTHOR> No idea why nobody is acting on it - maybe nobody else has thought of it yet. While the idea of there being attenuated strains out there is nothing radical, the idea of using them is.

Please everyone if you know someone you think might be able to help make this happen then spread the word. You are even welcome to steal the idea and claim it is your own :)

<comment><USER97> Have you considered sending this as a letter to a medical journal? I know it's not a "scientific article" per se, but many journals have a section dedicated to letters. For example, CMAJ (Canadian Medical Association Journal) considers such letters, and right now they're fast-tracking anything COVID-related: [https://www.cmaj.ca/](https://www.cmaj.ca/)

Best of luck!

<comment><AUTHOR> Yes I have, but the people I am trying to reach are not medical researchers, but people able to think outside the box.

</comment></comment></comment></comment><comment><USER98> This will happen naturally. No need for intervention. The longer it goes the better.

<comment><AUTHOR> This is true, but it might take a few hundred years. I think it would be better if we try and help the process along.

<comment><USER98> I'm not sure, but you might be greatly underestimating the rate of evolution for these virii. Generally it is ~10^9 faster than eukaryote evolution ([https://viralzone.expasy.org/4136](https://viralzone.expasy.org/4136)) and there are many (10^?) generations that occur in every host. Early selective pressure for fast replication makes it deadly, but late-stage selective pressure is to be transmissible through mild symptoms. The end game is that it becomes part of our DNA.

I might also mention that the virus doesn't really care about us. Mostly it's interested in infecting our bacteria. That's kind of a joke, but in reality, it says everything about how to control it.

<comment><AUTHOR> We have a pretty good idea how fast corona virus evolve. Yes there will be selection pressure for it to become less deadly, but this can take a long time. My proposal is how we can speed up this process.

</comment></comment></comment></comment><comment><USER99> > Singapore and Japan have recently seen this in action where they eased > restrictions and found the disease came back and they had to reintroduce > restrictions.

Poorly informed, Japan did not even have restrictions in the first place.

<comment><AUTHOR> Yes they did, just not the same as everyone else.

<comment><USER99> Closing schools and doing nothing else does not count much in terms of restrictions.

</comment></comment></comment><comment><USER100> This is genuis if it could be put to work.

Many possible vaccines for covid-19 are discussed in this paper [0] which is surprisingly accessible. There's a table [1] that depicts categorization of vaccine candidates and it does mention _attenuated virus_ as a possible solution, the one in development by Codagenix and The Serum Institute of India [2] expected in the second-quarter of 2022.

2022 seems to be an eternity away, and the problems, as the paper points out, with attenuated vaccines are:

1\. Requirement of a much wider phase 3 trial than other vaccine types.

2\. Very time consuming to create such viral strains in the lab.

There are overwhelming advantages working in its favour, though:

1\. Human vaccines using the same platform exist for other diseases.

2\. Existing infrastructure can be used to ramp up trials, approvals, manufacturing, and administration.

The proposed solution by Dr. Daniel Tillett here makes sense because it turns those disadvantages on its head-- a substantial number of people might already have been infected with proven mild inflection and the strain(s) can be isolated at a much faster clip!

[0] [https://www.cell.com/immunity/fulltext/S1074-7613(20)30120-5](https://www.cell.com/immunity/fulltext/S1074-7613\(20\)30120-5)

[1] [https://www.cell.com/action/showFullTableHTML?isHtml=true&ta...](https://www.cell.com/action/showFullTableHTML?isHtml=true&tableId=tbl1&pii=S1074-7613%2820%2930120-5)

[2] [https://seruminstitute.com/news.php](https://seruminstitute.com/news.php)

<comment><AUTHOR> I am not sure about the genius part, but it can be done. While a search for an attenuated virus might fail (there might not be one out there yet), it at least won't take long or cost much to look. Let's get started.

</comment></comment><comment><USER101> Any thought of writing a WaPo, NYT, etc. editorial? With an idea this potentially impactful and your credentials, seems like you'd have a good shot of being accepted.

<comment><USER102> Is that where decision makers are looking right now? I don't ask this to be snarky, but it seems that they post so many op-eds that it would get buried

</comment></comment><comment><USER103> At the end we'll all figure out "immunity" is the best defense. Miracles only happen when common sense takes over.

</comment><comment><USER104> Dear @danieltillett - Thanks for the thoughtful piece.

You noted on your post "live attenuated (oral) polio vaccine" but later wrote "Apart from the time it will take to develop, trial, and mass produce a vaccine (12-18 months), it is unlikely that any vaccine will be practicable."

So how do you imagine this solution being administered if not as a vaccine? Is the solution a Pox Party ([https://en.wikipedia.org/wiki/Pox_party](https://en.wikipedia.org/wiki/Pox_party)) with someone verified to have the harmless strain?

<comment><AUTHOR> A pox party would work. Given the strain will be infectious like the dangerous strains it is not going to be too hard to spread it around.

You can look at it from the other perspective - once identified it would be impossible to stop people spreading it around on their own. Let's say one of you friends got infected with this "safe" strain you would quickly head over to their home for a cup of tea and a good chat.

<comment><USER105> Much like the dangerous virus can mutate to a less harmful version of itself, isn't there a risk that the benign version could mutate back to a (more) dangerous form if spread this way?

<comment><AUTHOR> Not if you select a strain with the right mutation.

</comment></comment></comment></comment><comment><USER106> I'm late to the comment party but I wanted to say our hope might just be better treatment (and not a vaccine). Covid-19 doesn't have to fatal as long as hospitals _don't_ use their standard protocol. Here's what I mean: [https://www.evms.edu/media/evms_public/departments/internal_...](https://www.evms.edu/media/evms_public/departments/internal_medicine/EVMS_Critical_Care_COVID-19_Protocol.pdf)

<comment><AUTHOR> There is a large percentage of the world's population that can't access any hospital, let alone get treatment.

<comment><USER106> Does this treatment you can't get include vaccinations? I'm not sure what you're getting at. Anyway, hydroxychloroquine is on the list of World Health Organization Model List of Essential Medicines.[0] It's a widely available drug that can be found even in remote parts of Africa and India where malaria is prevalent. [0][https://apps.who.int/iris/bitstream/handle/10665/325771/WHO-...](https://apps.who.int/iris/bitstream/handle/10665/325771/WHO- MVP-EMP-IAU-2019.06-eng.pdf)

</comment></comment></comment><comment><USER107> So we need a DIY genome sequence kit. Where can I find a practical guide? What do I need?

<comment><AUTHOR> No we just need the samples and use the instruments we already have. Sequencing the viruses genome is not a complex problem technically.

</comment></comment><comment><USER13> This is the same thing as a vaccine (but without doing the safety due diligence). IMHO as a not-medical-professional, we'd be better off with just using one of the (dead) vaccine candidates early than with a _slightly_ attenuated live virus.

We actually started clinical trials of the Moderna mRNA vaccine in humans a month ago. We may have some early safety data. Better that than intentionally exposing people.

<comment><AUTHOR> No it is not. There is still safety data, it has just been done by nature and not by jabbing people in the arm with some experimental vaccine.

<comment><USER13> No, the safety data is not well controlled in this case. There are lots of ways to administer a vaccine, it doesn't have to be injection.

Look up the history of vaccination. Starting in the late 18th Century, people used to do this exact thing for early vaccinations: they found a naturally occurring, less pathogenic strain (for instance, cowpox[1] in the days of smallpox), and intentionally exposed people. This is exactly the same thing as a vaccine except less controlled and, ultimately, much less safe.

.

[1]The root of "vaccine" is "vacca," i.e. Latin for "cow," for this reason.

<comment><AUTHOR> Safety data can be gained from epidemiology studies. There is more than one way to work out if a treatment is safe and effective.

<comment><USER13> Epidemiological studies are much poorer than clinical trials. I'd rather have low-N but well controlled clinical trials than nebulous epidemiological studies.

<comment><AUTHOR> Of course, but in this pandemic we shouldn't let the perfect be the enemy of the good. Waiting for the perfect vaccine to be developed will have a very high cost. There are no easy options here.

</comment></comment></comment></comment></comment></comment><comment><USER108> The idea of voluntarily infecting the entirety of the population with a virus to prevent economic downturn seems a very dangerous idea to me. The purpose of society is to ensure the well-being of the people. It is not economic growth.

Furthermore, I see a few problems with that idea :

\- it seems very hard to create a truly harmless virus. Viruses still destroy cells to replicate, they cause immune system response, inflammation, what would happen to weak or immunocompromised people ?

\- if immunity through vaccines lasts 6 to 24 months, why wouldn't this be the case here too ? You'd still need to develop a vaccine or keep infecting people with new strains of this virus

\- why would the deadlier strain disappear ? Unless you also engineer the mild strain to be much more infectious, both strains would still spread equally in the population. Presumably the milder strain would be less symptomatic so it would in fact spread less

\- it's not demonstrated in what way economic downturn would be more harmful in the end. Economy is a means not an end.

<comment><USER109> > The purpose of society is to ensure the well-being of the people. It is not > economic growth.

"Growth" is not the issue, but economic prosperity and stability is immensely important with respect to the well-being of the people. Economic downturns also reliably cost lives in a huge amount of different ways.

I'll consider this idea to be pretty whack until people smarter than me think it's a good idea. But I hope we can come to terms that it's worth discussing taking _some_ health risks to limit economic downturns. "People's lives" vs "the economy" is a false dichotomy.

</comment></comment><comment><USER110> The author doesn't address how widespread the testing would need to be to accomplish this. What sample size is needed? Does it need to be geographically diverse? Does the human population tested need to be genetically diverse?

Also: Why is this faster than other methods of vaccine development already underway? Once developed, wide-scale manufacture & deployment is an enormous logistical challenge completely separate from R&D. Can this use existing vaccine manufacture & distribution channels?

It's difficult to really assess the viability of this plan without it taking into account many of these details. To my moderately-informed-outsider thinking (which lets face it, is the crowd the author was targeting by posting here on HN) it may suffer from the "ideas are easy, execution is hard" problem, because execution details apart from the actual R&D side are lacking. I'd like to hear more from the author on the topic though.

<comment><AUTHOR> I actually do address the numbers needed in the post. Yes you would want to sample as widely as possible in the ideal world, but more important is just getting the right samples.

The reason why this would be faster is the process of looking for the strain and identifying it as safe would generate data that would allow the regulatory authorities to approve its use.

Manufacturing would not be the limiting factor here.

<comment><USER110> I read the whole article through. Now I have done so twice. Maybe I have a blind spot, maybe I misunderstand something, but I don't see where you address the number of tests needed. Certainly you don't address the need (or lack thereof) for geographically & genetically diverse testing.

Your background also does not appear to contain detailed experience within the manufacturing and deployment side of vaccines, so I hope you'll forgive me if your lack detail on that end isn't mitigated by simply saying "Manufacturing would not be the limiting factor here" without further explanation.

You say you'd like to get this proposal in front of influential people, but why would Bill Gates assume the logistics are fine, not a problem, without you specifically addressing the issue?

And if I can't get answers to the questions I've raised after 1 full reading, one slightly faster reading, and an exchange with the author himself, then if I were a person of any influence I would not devote limited time to this proposal. Presumably you posted here to get such attention. Presumably you would engage a bit more and answer in greater detail if you knew I were someone who could help advance this in some way. (I'm not-- I have access to researchers in academe but no influence) But I don't see you getting the attention needed, not without a proposal that moves beyond the R&D phase _in significant detail_

Personally I find the lack of logistical details beyond the R&D and sequencing side of things indicate that your own business interests have you focusing on that end of the project to the detriment of other factors that need to be taken into consideration. Please note that I'm not saying you're doing this for the money: Only that your current area of professional endeavor is the area of the problem where you have focused your proposal, and the areas where it's lacking are not bolstered by your simple assertion of "they are are not a problem."

You have posted to an audience that is not automatically going to know how your R&D could be logistically deployed, but also an audience that knows ideas are easy, and execution is hard. If you wish to have your proposal widely accepted here, if you wish people here with connections to those who could influence anything, these are things you need to address.

<comment><AUTHOR> I address the number issue here.

 _With little cost we could sequence a few thousand viral strains, or even tens of thousands of strains, from positive test sample from asymptomatic and /or mild case until we find a virus strain with the right mutations to make it harmless and which could work like a vaccine._

The manufacturing issues are not really my strength or extremely relevant to the idea, but this involves a live virus so you just need to grow it up in large scale cell cultures. We have the infrastructure for this in place in the biotech industry. One of the positives of SARS-CoV-2 from the perspective of my idea is how contagious it is - you only need a small number of viral particles to achieve an infection. This makes the scaling much easier.

The bigger issue at this point is finding the attenuated strain strain.

<comment><USER110> You address how many viral strains could be obtained, you don't address how many people have to be tested to obtain that many strains. Since you would need to find asymptomatic people, and current testing prioritizes only those with relevant symptoms, you would need to test many, many people to obtain enough asymptomatic occurrences. You do not provide an estimate for that number. Or if my assumption is wrong, then please take it as a sign that people without your specific expertise may come away with the same assumptions.

I don't necessarily expect you to answer all my questions: I offer them, and hope you take them in the spirit in which they are intended, which is as a sort of peer-review process (Though I am certainly not your peer in these matters: I mention that as an analogy) because I believe you do have a compelling idea, but I believe for it to gain much traction there are details that must be filled in, and others that must be spelled out more plainly for outsiders to your field that don't have your knowledge.

I certainly appreciate you engaging with me and indulging my curiosity, and questions that perhaps seem to have obvious answers to someone with more expertise in the field than I have.

Thank you.

<comment><AUTHOR> In some countries they are doing a better job of testing the mild/asymptomatic cases (Germany, Singapore, South Korea are all examples). Even the USA these days is detecting plenty of positive mild cases.

We can use the the swab samples sitting in the testing facilities to do the genome sequencing.

Your response is quite common so I am writing a follow on post mon how this idea can be done in practice.

<comment><USER110> And to the extent we can rely on info from the US administration, Dr. Fauci commented (with some hedging) that Fall may bring widespread testing of the population at large for antibodies, which could be co-opted for this purpose as well.

I hope your proposal, and others proposing similar steps, win through. We need massively parallel efforts pursued. Not just to solve this current crisis, but to improve our overall global ability to rapidly reply to the next such problem. Best of luck to you.

</comment></comment></comment></comment></comment></comment></comment><comment><USER111> Isn't such a mutation just one SNP away from returning to virulence?

<comment><USER112> No. TFA makes clear that they are not looking for a SNP, but rather a deletion. In a comment further up, they suggest a deletion on the order of several hundred base pairs

</comment></comment><comment><USER113> He leaves out "developing a treatment" as an option. Why?

<comment><AUTHOR> Because it is a discussion about another topic and I wanted to keep the post short. Treatments are good, but this will not solve the problem.

</comment></comment><comment><USER114> The best would be to find a mutation that cannot jump from human to human .

Otherwise it could be dangerous if it mutates again to a more dangerous virus, even if not the original coronavirus (as you said we choose a mutation with a deletion).

<comment><AUTHOR> No. A major part of the value would be the host to host transmission as it would get herd immunity into those people not directly given the virus. Only a transmissible virus strain can drive the pathogenic strains to extinction too.

Large deletion mutations don't back mutate in practice.

</comment></comment><comment><USER115> The author is thinking that reversing a deleted zone mutation is hard, but it could be that a simple mutation of the weak strain make it deadly, so my question is: can you guarantee that a new mutation is not going to make this strain deadly?, also the more people with the new strain of the virus, the more the bad mutation could happen.

So I suggest looking for a strain for which we have a mean of killing the virus, that is a weak virus for which we have a general vaccine for expected mutations, if that is possible.

<comment><USER116> There are no guarantees in life, but the reason we don't have global pandemics constantly is that mutations that make a virus as dangerous as SARS-Cov-2 are quite rare.

<comment><USER29> There actually has been quite a lot of pandemics over the past 100 or so years. Covid-19 has yet to eclipse at least 3 of them. (1918, 1957, 1968)

</comment></comment></comment><comment><USER117> > We found, in our 788 confirmed COVID-19 patients, the decreased rate of > severe/critical type, increased liver/kidney damage and a prolonged period > of nuclear acid positivity, when compared with Wuhan.

So how are we gonna deal this increased liver damage then, if we are actually gonna use this less pathogenic branch of the virus as a quasi-vaccine?

Is there way to reengineer this virus so that it would be less kidney/liver damaging?

</comment><comment><USER89> Very interesting post. One way to get this talked about more widely is to somehow get it in front of Trump.

</comment><comment><USER118> IIRC this idea is the origin of the word "vaccine" - from vache, French for "cow" - people used to intentionally get infected with cow pox 300 years ago, and it would confer protection against smallpox. On phone so hard to check and link.

</comment><comment><USER119> >> The polio, ... vaccines are all live attenuated viruses.

IIRC, the USA came very close to eliminating polio by switching between live virus vaccines and killed-virus vaccines several times.

</comment><comment><USER120> I see one potential drawback to this (as opposed to a vaccine), and that is the impossibility to protect immunodeficient subjects: if you have an effective vaccine you can be fairly certain that people with leukemia or full blown AIDS can be protected by herd immunity when surrounded by people who have been vaccinated. In this case it's not clear to me whether this would work. I have to say I'm no virologist, but I find the fact that this milder strain can still propagate on its own some kind of a double edged sword.

Maybe someone who knows more about this than I do could comment.

<comment><USER121> Right now it is also impossible to protect immunodeficient subjects, but herd immunity could help. I don't think the author ever says, "We should do this and only this in lieu of a vaccine."

The argument is, "This can be done now, or soon, while a vaccine will take 12 - 18 months, if not longer."

<comment><USER120> It's not quite the same ethically: for all of this to work you should make this attenuated virus spread faster than the more deadly ones, so there is a positive act to be made which goes directly against the Hippocratic oath (do no harm).

Immunodepressed subjects right now are protected by isolation and by the fact that right now a smallish percentage of the general population is an asymptomatic carrier, if we were to start spreading this actively those variables would change.

</comment></comment></comment><comment><USER122> It is commendable to search for solutions to the Corona virus.

But the author is doing himself a disservice by saying that tens of millions of people worldwide will die.

And why is it a bad thing to have to be vaccinated on a yearly basis, poor African countries have not been hit hard that is a fact.

The areas being hit the hardest can afford to be vaccinated yearly and is accustomed to it with the yearly flu shot.

Other than that, keep up the good work !

<comment><USER123> You're ignoring the fact that this virus Is an order of magnitude more lethal than the flu, and I would guess that most individuals in poorer countries skip the vaccine altogether.

<comment><USER122> It has only been proven lethal for very old and people with chronic illnesses.

Those people should stay at home and practice distancing.

<comment><USER25> Are you just igoring news that fly in the face of what you're stating here? Have you looked at the current state of NYC?

<comment><USER122> My wording could be better I admit and yes I have looked at the NYC numbers that show 86% of deaths are due to underlying illnesses, source: [https://eu.usatoday.com/story/news/health/2020/04/07/new- yor...](https://eu.usatoday.com/story/news/health/2020/04/07/new-york- coronavirus-deaths-data-shows-most-had-underlying-illnesses/2960151001/)

Being old and having underlying illnesses is by far the biggest reason for deaths in NYC, with Hypertension and Diabetes being among the top risk factors.

Worryingly, in Sweden in the capital Stockholm, around 15% of the staff caring for the elderly have had Corona virus.

</comment></comment></comment></comment></comment><comment><USER124> I sent this article to a vaccine researcher I know, here are his comments (I have his permission to share this):

TLDR the virus mutates too quickly for this to be safe.

" There are many ways to make vaccines, and the oldest one is to take the wild-type pathogen, and either 'break' it ('attenuate it'), or find an example in nature that's messed up and can't cause disease.

The initial smallpox vaccine was cowpox: Close enough to human smallpox that it elicited protective immune responses, but too maladapted to humans that it couldn't thrive in us, and would be caught by the slow-walking cops of our immune system.

The strategy used for many of the 1950s/60s-era vaccines was to isolate the disease-causing pathogen, then in a laboratory force it to grow in progressively more-messed-up circumstances. This would drive evolution of the pathogen to mis-adapted freaks. For example, the mumps isolate was from the daughter of the Merck scientist (Maurice Hilleman), and he grew it in cow cells, then lizard cells, then insect cells (or somesuch, I don't know exactly). By the end of the process, the thing could still infect humans, but just BARELY.

Nowadays, with molecular biology, we can rationally design the 'attenuations', and do knock-outs or modifications.

Which brings me to low-virulence wildtype isolates of SARS-CoV-2 (S2): The root problem here, as with HIV, is it's a super-fast-evolving RNA virus. Sure, a particular isolate might be low-virulence NOW, but give it a few weeks on a cruise ship and – viola! – nasty bugger ahoy!

When SARS-CoV-1 broke out, years back, it had a high lethality and freaked out the public health experts at the time (in fact, we were writing proposals to get into the research, but then it got contained). At that time, efforts were initiated to make a vaccine, based on the observation that all that was needed with the Bcell production of 'neutralizing antibodies'. This is the long standard, matching most existing vaccines. So it was a low-weight lift, for vaccine developers (relatively easy-peasy). The project got pretty far along, but then stopped when SARS-CoV-1 disappeared as a threat.

When MERS, then SARS-CoV-2 came along, they resurrected the previous, promising design, based on a slow-evolving vector. But in the case of S2, they discovered that the targeting receptor usage of S2 was significantly different, so the design required a significant re-tune. Even so, the Chinese (I think) did it, injected the first people several weeks back, and I don't think it works well (too early for formal reports).

S2 is nasty, as HIV is. It is using evolution against us. And because its hypermutable (like the influenza viruses), it's going to be nearly impossible to make one vaccine that works cycle after cycle. It will continue to evolve, but the subsequent cycles will probably have lower lethality than this first pass (which was completely novel to the human immune system, so we had no 'herd immunity' protection). Going forward, it will be hard for highly- virulent forms to transmit if they kill their hosts too quickly, which will select for less-virulent forms.

The trick is to stay alive during this pass. The only mechanism we have to do this is to not get infected. The only way to do that is to not expose ourselves to infected people, or the things they've touched.

We're back to how things were in the 1800s. Better than no science, but about the same as post-epidemiology/cell-theory-of-disease (1890s)

But as I said, this vaccine should be RELATIVELY easy to develop. It doesn't have to be perfect, it just has to blunt viremia (so that the global pneumonia it causes in your upper/lower respiratory system doesn't cause aveoloar collapse. In other words, even working a little bit will probably massively lower the death count.

But even an easy-peasy vaccine will take 18 months. There's just no getting around that, unless you want to inoculate 5 billion people with something that might make the pandemic worse."

<comment><AUTHOR> Can you ask this person to write to me directly as I think they have missed what is novel about my proposal and have instead focused on what is not.

</comment></comment><comment><USER125> The idea that naturally mild strain of the coronavirus would provide a durable benefit, but a human-created vaccine would not, seems to me like an idea that needs a lot more explanation. The mechanism of immunity should be the same between those two.

<comment><USER126> The main argument here is that finding a mild strain (and having it tested implicitly by virtue of it infecting many humans) could be faster than developing a human-created vaccine.

I don't have any credentials in this field, but IMHO we should attack the problem from all possible angles, including the search for a natural, less harmful strain.

<comment><USER125> He says:

> Apart from the time it will take to develop, trial, and mass produce a > vaccine (12-18 months), it is unlikely that any vaccine will be practicable. > The reason why is immunity to respiratory viruses (like corona) doesn't last > long – 6 months to 2 years. We would have to keep vaccinating everyone in > the world every year (or maybe every 6 months if we are unlucky). This just > isn't going to work in the real world (especially poor countries) and is one > of the reasons we don't have a vaccine for the coronavirus strains that > cause the common cold. Unless we can drive the current dangerous SARS-CoV-2 > strains to extinction we are going to have a problem with this disease > indefinitely.

Every one of these objections also applies to a less harmful strain.

For example, one reason vaccines don't confer durable immunity to many respiratory infections is because the infectious agents change over time, migrating away from the vaccine response. Well, by the same token, a less deadly strain of such an infectious agent would also change over time at the same rate.

On the other hand if we think a naturally occurring strain would provide stable immunity over a long time, then a human-created vaccine would also be stable for a long time.

There is nothing magical about naturally occurring strains. They work in the body exactly the same way vaccines do. (Which is of course why vaccines work in the first place.)

<comment><AUTHOR> The "magical" part is nature has run the experiments we aren't yet ready to run with vaccines. Time really is an important issue.

<comment><USER125> Nature may have run enough experiments to know that the less deadly strain is as safe as a vaccine, but she won't just tell us that. We would have to discover it for ourselves with the same scientific method we use to interrogate vaccine candidates. Which BTW is the time-consuming part... we already have some candidates.

This matters because if someone were to do anything to promote or help others infect themselves with the strain... that person or company could face significant civil liability if the strain turns out to not be safe for everyone. Even one wrongful death suit can ruin your day.

Vaccine liability is "manually managed" via federal legislation. Encouraging people to have infection parties is not.

<comment><AUTHOR> Yes we use the scientific method of epidemiology - has been working since John Snow used it to determine that there was a cholera problem with the Broad Street Pump [1].

I am not encouraging anyone to do anything other than look for a natural attenuated strain. This point seems to be missed time and time again.

1\. [https://en.wikipedia.org/wiki/1854_Broad_Street_cholera_outb...](https://en.wikipedia.org/wiki/1854_Broad_Street_cholera_outbreak)

<comment><USER125> If you're proposing an investment of effort to find new information, it's absolutely fair game to ask what we will do with that information--how we will benefit from it.

a) We find a naturally attenuated strain and do nothing to promote or spread it.

b) We find such a strain and treat it like a vaccine candidate with all the testing.

c) We find such a strain and treat it like a vaccine candidate but without all the testing.

If someone does a) or b) they are on solid legal and scientific ground, but arguably have not created any new benefit beyond what is already happening to develop a vaccine.

Whoever does c) would certainly deliver a benefit in terms of speed... but if they cause any unexpected harm, would be exposed to legal liability.

I guess my fundamental question is whether the hard part of developing a vaccine is attenuating the virus or proving such attenuation is safe. Epidemiology can help us find natural versions of the former, but it can't help us with the latter.

Epidemiology cannot satisfy a question of safety. It can only identify risk factors, as John Snow did with the water pump. If your idea succeeds, at best we will be able to say "this strain seems to be a low risk factor for serious illness or death in this population." Then what?

The critical moment for cholera was to run an experiment: remove the pump handle and see what happens. But in the case of vaccines or vaccine-like strains, we are not talking about an experiment to _remove_ a risk factor, we are talking about _spreading_ a risk factor after properly qualifying its risk as low. That is much harder to do. The only way is to run a bunch of experiments.

<comment><AUTHOR> No matter what is done or not done there is risk. This is the nature of this problem. I am of the belief that the more options you have the better. If there is an attenuated strain out that has infected a large number of people we should look for it. What we do with it if we find it is a political question, not a scientific one.

</comment></comment></comment></comment></comment></comment></comment></comment><comment><USER110> I'm always skeptical simple solutions proposed to solve complex problems. Unintended consequences or unanticipated roadblocks are often an issue.

In this case, the author _might_ under estimate the logistics involved in getting this done. At a minimum, the author does not adequately address the logistical challenges of this endeavor in the context of already challenging testing environments. The "quick & cheap" aspect of this is therefore a claim without support.

It might be a promising line of endeavor, and we should pursue multiple parallel initiatives, but the resources needed to pursue this are highly correlated with the resources needed to perform many of the other initiatives that are also promising. There is a bottleneck. Why should this take precedence over other already promising lines of inquiry?

<comment> the-pigeon I don't think this is a very simple solution at all.

It's really just a different vaccine approach and this isn't the first person to suggest it. It's been talked about online since February if not before.

Not to say I don't think it's a viable idea and I do think it needs more visibility. As the author states this has worked for other diseases.

<comment><USER110> The author proposes it as "quick & cheap" and leaves out nearly all logistical considerations. To my thinking, that is an overly-simple proposal.

<comment><AUTHOR> Something can be quick and cheap without being easy. The proposal is far from easy.

The post leaves out a lot of technical details that the average non-scientist doesn't need to know.

</comment></comment></comment></comment><comment><USER127> I'm glad people are realizing that all this social distancing is merely a pause button on the virus. Once we press play on society, exponential growth will happen again and we will have effectively rolled back the clock until we reach herd immunity through things like the OP's suggestion.

At least this next time we'll hopefully have more PPE.

<comment><USER128> I'd much rather live in a world where everyone is required to wear masks all the time than live in a world where we are all told to stay home all the time.

I believe it's also well established that any measures taken to slow the spread of a new virus will always result in fewer total deaths, in that sense quarantining is much more effective than just being a pause button.

<comment> grey-area This is a false dichotomy. Masks or gloves as worn by ordinary people are nowhere near effective enough to mean lockdowns could end. They're very effective in clinical settings with proper ppe head to toe and procedures for taking them off outside the dirty ward, but there's no way most people can stick to those, nor keep their houses/shops clean enough.

 _I believe it 's also well established that any measures taken to slow the spread of a new virus will always result in fewer total deaths_

In the sense that they prevent a healthcare system being overwhelmed yes, in any other sense no, they are very much just a pause button for the spread of the virus, not a cure.

<comment><USER129> We wouldn't insist that people 'stop breathing' to prevent the spread of coromaviris. It's only somewhat different to insist that we all stop living and working.

Masks and gloves, plus generally keeping 6ft apart and routinely testing and contact tracing/quarantining infected individuals... what's the effective rate there? 95%? The modern medical establishment would move heaven and Earth, and incur thousands of dollars per person to get that last 5%. Most of us routinely ignore them in this regard, with respect to our own personal health, as we live our daily lives.

There just isn't a lot of evidence for the case that the choice is shutting the economic or killing millions.

<comment><USER130> > There just isn't a lot of evidence for the case that the choice is shutting > the economic or killing millions.

Which is why we have models, no?

<comment> _-___________-_ Yes, although reality seems to be disagreeing with the models more and more. You have countries in southeast Asia with community transmission but no lockdown, and countries in Europe with the military enforcing a strict lockdown, and the latter are far worse off in terms of hospital admissions and deaths per capita than the former.

<comment><USER130> Did the European countries not get their transmissions before they implemented a lockdown?

My understanding is it takes 1 - 3 weeks to see the effect of a lockdown?

</comment></comment></comment></comment></comment></comment></comment><comment><USER131> Finding an attenuated strain that spreads as easily but is less deadly does sound like our best hope. Such a strain would "crowd out" the deadly strain, effectively blocking it from causing harm.

If life was a Star Trek episode, Picard would be saying "Make it so" right about now.

<comment><USER132> "Captain's log, stardate 73740.9. The Enterprise has taken on board a distinguished Federation virologist, dr. Daniel Tillett, to help him with his search for a less harmful strain of the virus that's currently ravaging several planets in Federation space. The doctor is confident that such an attenuated strain could be used to swiftly end the ongoing pandemic."

I would watch that episode. Hell, I'd watch any new episode; unfortunately, the only proper Star Trek we've had since Enterprise stopped airing is The Orville.

<comment><USER133> And then it turns out similar to "Ethics", where the virologist's work is questionably founded and potentially quite dangerous, we get a Picard speech about how sacrificing some to save others is wrong, Data and Crusher technobabble up a treatment that doubles as a vaccine, the photogenic kid gets saved at the bottom of the fourth act, Admiral Nechayev and Picard fence a bit, credits.

Pretty wild to count Enterprise as "real Trek", but not Discovery. And hey, TNG was seminal and I loved it growing up too, but let's be real, it's showing its age quite badly these days.

<comment><USER134> I saw a few clips of ST:Discovery and nearly had an apoplexy. When the ship spins (rolls) on its longitudinal axis and disappears (using the "spore drive"...) I pretty much lost my mind for a moment.

Then it reappears with a flash _that illuminates the nebula in the background_. There are no clouds in space. Nebulas are big, really big. It would be light-years away. But the ship's photo-backwash lights it up like a flash bulb! I know Star Trek isn't hard sci-fi, but that's pathetic.

And the "spore drive"!? Who thought that up? (I know about mycorrhiza and all that, I'm not ignorant) The universe is pervaded by invisible intangible cosmic fungus? That somehow enables FTL teleportation? And keeps people alive in limbo after they die? That might be Lovecraft but it's not Roddenberry.

And they named the "astromycologist" character after the real guy!? (Paul Stamets) Did they _ask_ him? That's just so weird.

To me it feels like it's made to mock Star Trek fans. Watching it (just for about ~4 minutes) made me feel like the network and producers are just mocking me. (And not in a good way. I _love_ Galaxy Quest, because it's obviously made with love and, yes, respect for the show(s) it mocks. When Sigourney Weaver loses it and starts ranting about how it's a dumb episode, nobody would design a space ship with giant crushers and fire spouts... Yeah, it's awesome!)

Discovery is more cartoonish than the actual cartoon. ( [https://en.wikipedia.org/wiki/Star_Trek:_The_Animated_Series](https://en.wikipedia.org/wiki/Star_Trek:_The_Animated_Series) )

I gotta agree that _The Orville_ carries the torch forward far far better than these new Star Trek shows & movies.

<comment><USER135> The spore drive is a correctly-formatted and notarized petition to Juffo-Wup.

The flash does not originate at Discovery and propagate outward as light, but begins before the ship appears, from a diffuse source, constructively interferes at Discovery's normal-spacetime discontinuity, and generates a holographic illusion between the observer and the nebula that just appears to be a flashbulb reflection.

Every Star Trek problem may be resolved by sufficient application of technobabble (a.k.a. [TECH] in the script). It's space opera. Apply the MST3K rule. (It's just a show; I should really just relax.)

The space-mushroom dimension is the same as the gate network from Stargate SG-1, or the wormhole-traversal tech and Leviathan starburst from Farscape. It's the plot conceit that allows the cast to instantly move from one set to another without any of the boring and unremarkable travel time. The exact nature of the instant-transport is dependent on the dramatic series plot arcs that the show-runners came up with in case they ever got past the pilot episode. The cool CGI visual effect used to signal to the viewer that sci-fi is happening now is flawed. Not everyone can pull off the Stargate-opening vortex.

Discovery and Picard are very much darker than pure Roddenberry, in that they portray The Federation as something far short of a perfectly ethical Utopia. In my opinion, this is a decision that allows for a far wider range of character development. An imperfect Starfleet can employ a monstrous starship captain that murders to keep its secrets. Klingons can be more than just a racial stereotype to be used as a script proxy for 1960s Russia (and the language has already been constructed, so might as well use it).

<comment><USER132> > _In my opinion, this is a decision that allows for a far wider range of > character development._

This may be the core disagreement, I (and I'm guessing GP) don't like this decision. Star Trek was an unique word in sci-fi (at least on-screen sci-fi) _because_ of that bright idealism, that utopia. "An imperfect Starfleet can employ a monstrous starship captain that murders to keep its secrets"[0], and done regularly, this makes the show just another run-of-the-mill sci-fi.

(I do like how Klingons were fleshed out as a species in DIS, though; it's my favorite aspect of the show.)

There's plenty of sci-fi shows and movies. Star Trek, in its TNG to ENT era, was unique in terms of positivity and optimism. I miss that, because (with the possible exception of the Orville) there's nothing like that anymore.

\--

[0] - To the extent that Sisko once facilitated murder to keep a secret hidden, this infamous DS9 episode works precisely because it's a one-off situation that's in a stark contrast with the overall behavior of the character and setting of the show.

<comment><USER134> Bingo! Take away Roddenberry's vision of a better future and you've got Babylon 5, eh? Like I mentioned in a sib comment, it turns out that this was a tension going right back to the original series. It's hard to write!

(You like the Klingons? To me they seemed derivative of (LotR) Orcs but I haven't spent time to really know.)

> I miss that, because (with the possible exception of the Orville) there's > nothing like that anymore.

I've been thirsty as hell for some good (video) sci-fi for a while now and have been looking and (IMO) you're correct.

[https://en.wikipedia.org/wiki/List_of_science_fiction_films_...](https://en.wikipedia.org/wiki/List_of_science_fiction_films_of_the_2010s)

(And don't get me started on the blurring of the "sci-fi" genre. Superhero movies are not sci-fi. Sharks attacking are not sci-fi even if they have lasers on their heads, or six heads, or swim through ice. Fast & Furious isn't sci-fi. Harry Potter isn't sci-fi. (WTF Sy-fy channel!?) Zombies aren't sci- fi. Nor vampires, nor bigfoot, nor giant animals. Godzilla isn't sci-fi. I'm just ranting... ignore me. Swords and magic: not sci-fi. ...okay I think I'm done...)

<comment><USER132> > _Take away Roddenberry 's vision of a better future and you've got Babylon > 5, eh?_

I'd wish! I find B5 to be great in a different way than Star Trek. It has one of the deepest and most interesting stories I've ever seen explored in sci-fi on the screen. I wish there was another show like this. Alas, it seems that if you take away a vision for a better future, the shows you get today are cookie-cutter action flicks. They're sometimes fun to watch, but I don't feel enriched in a way I felt after Star Trek or B5.

> _(You like the Klingons? To me they seemed derivative of (LotR) Orcs but I > haven 't spent time to really know.)_

Not initially, and not from the looks - though the series did manage to (spoiler alert) turn them into what you'd expect to see in TNG in the latter seasons.

What I liked about the Klingons in DIS is that they didn't feel like space brutes who value violence and hate the Federation for no reasons. In DIS, they had a good reason, that resonates with people today - cultural imperialism. They went to war with the Federation because they felt it's the only way to protect their cultural identity, as they perceived UFP to be a civilization that conquers in times of peace, through slowly infusing everyone with their views and values. The DIS Klingons have seen that as a threat to the survival of their species' identity. And put that way, it's a very believable as a justification for conflict.

> _And don 't get me started on the blurring of the "sci-fi" genre. (...)_

In complete agreement (though I liked Iron Man 1; it was more serious than other MCU movies, and also scratched my tech porn itch). My additional complaint is the pressure put on inter-character drama and general "character development". As I often repeat, if I wanted to watch the deep emotional struggles of people and their relationships, I'd pick _literally any other literal /movie genre_. Sci-fi (and to some extent fantasy) is unique, because it can get away with extensive world building and exploring ideas that are hard to explore otherwise. It serves as a real-life holodeck simulation. And I'd prefer my sci-fi to focus on that.

<comment><USER134> In re: B5, I've a confession to make. I never watched it. I've seen a few episodes, of course, but I was homeless at the time it ran and I've just never gotten around to it since. I should probably go order the DVD set right now, eh? I know a teeny bit about the story and characters, and I've heard that it was written as a single super-arc, which sounds awesome.

Those Klingons sound more interesting than what I was afraid they were like.

> My additional complaint is the pressure put on inter-character drama and > general "character development". As I often repeat, if I wanted to watch the > deep emotional struggles of people and their relationships, I'd pick > literally any other literal/movie genre. Sci-fi (and to some extent fantasy) > is unique, because it can get away with extensive world building and > exploring ideas that are hard to explore otherwise. It serves as a real-life > holodeck simulation. And I'd prefer my sci-fi to focus on that.

I couldn't have put it better myself. So much this. And I find it doubly exasperating because there's so much written science-fiction to draw on, going back decades! Where is the movie/mini-series of "Moon is a Harsh Mistress"? ...oh! [https://en.wikipedia.org/wiki/The_Moon_Is_a_Harsh_Mistress#F...](https://en.wikipedia.org/wiki/The_Moon_Is_a_Harsh_Mistress#Film)

> In 2015, it was announced that Bryan Singer was attached to direct a film > adaptation, entitled Uprising, in development at 20th Century Fox.

I wonder if that's still happening?

I think "The Legacy of Heorot" would work really well as a movie.

I know it's kind of a cliche (and more work than it seems) but I kind really want to start a sci-fi production house... just a little one. Y'know? Specializing in hard sci-fi mostly, but not neglecting the other, uh, dimensions worth exploring.

</comment></comment></comment></comment></comment></comment></comment></comment></comment><comment><USER136> Could we already start with this? There are almost no deaths in young people, so how about we send the youth to a Corona Summer Camp for a week or 3?

[https://www.worldometers.info/coronavirus/coronavirus-age- se...](https://www.worldometers.info/coronavirus/coronavirus-age-sex- demographics/)

<comment><USER137> How much % of young people end up in ICUs or hospital ? The numbers are always elusive about that.

<comment><USER136> According to CDC :

Age group (yrs) 0–19 (123 cases) Hospitalization 1.6–2.5 ICU admission 0 Case- fatality 0

[https://www.cdc.gov/mmwr/volumes/69/wr/mm6912e2.htm](https://www.cdc.gov/mmwr/volumes/69/wr/mm6912e2.htm)

<comment><USER137> Thanks a lot!

</comment></comment></comment></comment><comment><USER138> This entire article is a waste of time from the beginning.

The "two strain" theory was debunked the very next day as bad science.

[http://virological.org/t/response-to-on-the-origin-and- conti...](http://virological.org/t/response-to-on-the-origin-and-continuing- evolution-of-sars-cov-2/418)

I can't believe that a month later, this bad science is still being circulated, by a purported PhD and former professor.

<comment><AUTHOR> I can't believe you think I am arguing for the "two strain" theory. My proposal has absolutely zero to do with two strains.

<comment><USER139> "As of 2nd March 2020, there are 111 nonsynonymous mutations that have been identified in the outbreak, these have been catalogued here in the CoV-GLUE resource 504 and can be visualised in Figure 1. At current, there is no evidence that any of these 111 mutations have any significance in a functional context of within-host infections or transmission rates."

The proposal requires identifying new strains among symptomatic and asymptotic people, find strains that only occur with asymptomatic people, start infecting people with that strain, verify they are at lower risk. Then scale this up to ever larger populations.

If we knew of a less dangerous strain then sure you can start down that path. However, at this point there is significant evidence such a strain does not exist due to the extremely slow mutation rate, making this mostly wishful thinking.

<comment><AUTHOR> Of course there may not be a strain with the right mutations out there, but should this be a reason for not looking. Nobody has been systematically looking for less dangerous strains (that I know of). My proposal is we look given it will be quick and cheap.

</comment></comment></comment></comment><comment><USER140> > Aren't most people who have mild/asymptomatic cases infected with a > dangerous strain?

> Yes. Almost all (>99.9%) of people who are infected (and have a mild case) > are infected with a dangerous strain of the virus, they just happen to have > an immune system that can control the virus well. With COVID-19 a mild case > does not mean you are infected with an attenuated strain – for most people > with a mild case if they happen to infect a person with preexisting > conditions or who is old, that person will be at a high risk of dying. A > mild case does not equal a harmless strain.

Even if the weak-strain hypothesis holds water (which remains to be seen), the proposal is predicated on something that's physically impossible to do. Test large numbers of people. Hundreds of millions or even billions.

Then, given those tests, find the weak strains.

That's also the minimum needed to "re-open" the country.

If we could test 20-30% of the population, we'd be in great shape. But we can't and may not ever be able to.

Even if you can test that many, you've got to prove that the weak strain is harmless. Then you've got to figure out how to administer doses safely.

So the solution must work within those parameters. And the only practical option is a vaccine.

> The major risk is the virus we think is safe is not 100% safe. While we can > use community spread of the identified strain to estimate how safe it will > be (i.e. if it has infected 1000 people and none have got seriously ill then > we should have a pretty good idea that it is safe), but our knowledge will > be incomplete. We can of course spend the next few years testing and > trialling, but if we do this by the time any strain is shown to be 99.999% > safe (not even the polio vaccine is 100% safe) we will have all got COVID-19 > and the world's economy will be a smoking ruin.

This guy is absolutely bonkers, or pulling a Swift.

He's proposing the (forced?) infection of a large portion of the population with a live virus that has been through none of the safety protocols established over many decades of catastrophic failures.

This is not how drug testing works. This is not how public health works. This is not how you assess safety. This is not ethical.

This is tech bro medicine at its absolute worst.

</comment><comment><USER141> This is a repost since last time you asked how to reach Bill Gates.

<comment><USER142> I invited danieltillett to repost [https://news.ycombinator.com/item?id=22798626](https://news.ycombinator.com/item?id=22798626). My reason is to build up a body of community reactions to the idea, that can serve as a basis for deciding whether to promote it further. I don't know Bill Gates, but I do know some people inside YC who are hard at work on this problem, and maybe they know someone who knows someone, etc.

If it's just a repetition of the previous thread, I'm sorry. Repetition isn't good and that wasn't my intention.

<comment><USER143> I know you often do so anyways, but perhaps these kinds of reposts deserve a comment explaining their circumstances.

<comment><USER142> I don't think this would add much value, because it would attract attention away from submissions to the meta-business of their provenance on HN.

I'm wary of adding bookkeeping facilities for that reason generally.

<comment><USER143> Fair enough; just thought I'd mention it because the lack of such bookkeeping seems to attract attention as well.

<comment><USER142> It certainly does. It's a perennial sore spot, understandably. I just fear that trying to eliminate that pain would cause more pain.

</comment></comment></comment></comment></comment></comment><comment><USER144> The author should test this idea on himself and demonstrate skin in the game.

<comment><AUTHOR> I am more than happy to be exposed to an attenuated SARS-CoV-2 strain, but first we have to find one. My idea is how we can find one.

<comment><USER145> I think it would be pretty easy for you to find a strain. Start licking subway poles, then see what happens! Just kidding. Stay safe. ;)

<comment> _-___________-_ If the virus managed to stay alive on a subway pole for very long, it's probably not very attenuated, no?

</comment></comment></comment></comment><comment><USER146> There's multiple people here suggesting everyday people spread a possibly less lethal strain, in ways that will likely spread every other contagious disease they also had.

I think this post needs to be removed now</comment>